U.S. patent application number 12/570355 was filed with the patent office on 2010-02-25 for pyrimidine hydrazide compounds as pgds inhibitors.
This patent application is currently assigned to SANOFI-AVENTIS. Invention is credited to Suzanne C. Aldous, Michael W. Fennie, John Z. Jiang, Stanly John, Lan Mu, Brian Pedgrift, James R. Pribish, Barbara Rauckman, Jeffrey S. Sabol, Grzegorz T. Stoklosa, Sukanthini Thurairatnam, Christopher L. Vandeusen.
Application Number | 20100048568 12/570355 |
Document ID | / |
Family ID | 39494539 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100048568 |
Kind Code |
A1 |
Aldous; Suzanne C. ; et
al. |
February 25, 2010 |
PYRIMIDINE HYDRAZIDE COMPOUNDS AS PGDS INHIBITORS
Abstract
This invention is directed to a compound of formula (I):
##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L.sup.1
are as defined herein, a pharmaceutical composition comprising the
compound, and the use of the compound to treat allergic and/or
inflammatory disorders, particularly disorders such as allergic
rhinitis, asthma and/or chronic obstructive pulmonary disease
(COPD).
Inventors: |
Aldous; Suzanne C.;
(Gillette, NJ) ; Fennie; Michael W.; (East
Stroudsburg, PA) ; Jiang; John Z.; (Hillsborough,
NJ) ; John; Stanly; (Basking Ridge, NJ) ; Mu;
Lan; (Basking Ridge, NJ) ; Pedgrift; Brian;
(Flemington, NJ) ; Pribish; James R.; (Piscataway,
NJ) ; Rauckman; Barbara; (Flemington, NJ) ;
Sabol; Jeffrey S.; (Bridgewater, NJ) ; Stoklosa;
Grzegorz T.; (Hillsborough, NJ) ; Thurairatnam;
Sukanthini; (Bedminster, NJ) ; Vandeusen; Christopher
L.; (East Windsor, NJ) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206, MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
SANOFI-AVENTIS
Paris
FR
|
Family ID: |
39494539 |
Appl. No.: |
12/570355 |
Filed: |
September 30, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
PCT/US2008/058347 |
Mar 27, 2008 |
|
|
|
12570355 |
|
|
|
|
60909171 |
Mar 30, 2007 |
|
|
|
Current U.S.
Class: |
514/235.8 ;
514/242; 514/252.14; 514/256; 544/121; 544/122; 544/182; 544/296;
544/333 |
Current CPC
Class: |
A61P 27/14 20180101;
C07D 403/14 20130101; A61P 29/00 20180101; C07D 403/12 20130101;
C07D 417/14 20130101; C07D 413/12 20130101; A61P 37/00 20180101;
C07D 239/28 20130101; A61P 11/06 20180101; A61P 43/00 20180101;
A61P 37/08 20180101; A61P 11/00 20180101; A61P 27/16 20180101; A61P
11/08 20180101 |
Class at
Publication: |
514/235.8 ;
544/333; 514/256; 514/252.14; 544/122; 544/182; 514/242; 544/121;
544/296 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 401/14 20060101 C07D401/14; A61K 31/506 20060101
A61K031/506; A61P 29/00 20060101 A61P029/00; A61P 37/00 20060101
A61P037/00; A61P 37/08 20060101 A61P037/08; A61P 11/06 20060101
A61P011/06; A61P 11/00 20060101 A61P011/00; C07D 403/12 20060101
C07D403/12; A61K 31/496 20060101 A61K031/496; C07D 413/14 20060101
C07D413/14; A61K 31/53 20060101 A61K031/53; C07D 417/14 20060101
C07D417/14; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound of formula (I): ##STR00234## wherein: R.sup.1 is
(C.sub.1-C.sub.6)-alkyl optionally substituted one or more times
independently by halo, hydroxy, (C.sub.1-C.sub.6)-alkoxy, or
(C.sub.1-C.sub.4)-haloalkoxy, or (C.sub.3-C.sub.6)-cycloalkyl, aryl
or heteroaryl, each of which is optionally substituted one or more
times independently by halo, (C.sub.1-C.sub.6)-alkyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.4)-haloalkyl or
(C.sub.1-C.sub.4)-haloalkoxy; R.sup.2 is hydrogen or
(C.sub.1-C.sub.4)-alkyl optionally substituted one or more times by
halogen; R.sup.3 is hydrogen, alkyl, aryl or heteroaryl, R.sup.4 is
hydrogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, arylsulfonyl,
heteroarylsulfonyl, --C(.dbd.O)--NY.sup.1Y.sup.2,
--C(.dbd.S)--NY.sup.1Y.sup.2, R.sup.5, --C(.dbd.O)--R.sup.5 or
--C(.dbd.S)--R.sup.5, wherein the aryl, heteroaryl or heterocyclyl
moiety is optionally substituted one or more times independently by
R.sup.6, or R.sup.3 and R.sup.4 together with the nitrogen atom to
which they are attached form heterocyclyl, heterocyclenyl,
heteroaryl, arylheterocyclyl, arylheterocylenyl,
heteroarylheterocyclyl, heteroarylheterocyclenyl,
heterocyclylheteroaryl or heterocyclenylheteroaryl, each of which
is optionally substituted one or more times independently by
R.sup.6; R.sup.5 is cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which
is optionally substituted one or more times independently by
R.sup.6; L.sup.1 is a bond, --O--, --C(.dbd.O)--,
--NH--C(.dbd.O)--, or (C.sub.1-C.sub.2)-alkylene optionally
substituted one or more times by halo; R.sup.6 is cyano, nitro,
halo, hydroxy, carboxy, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2N--C(.dbd.O)--, Y.sup.1Y.sup.2N--SO.sub.2--, acyl,
acyloxy, alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl,
alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is
optionally substituted one or more times independently by: acyloxy,
halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl,
Y.sup.1Y.sup.2N--, Y.sup.1Y.sup.2N--C(.dbd.O)--,
Y.sup.1Y.sup.2N--SO.sub.2--, aryl, aryloxy, aroyl, heteroaryl,
heteroaryloxy, heteroaroyl, heterocyclyl, heterocyclenyl,
cycloalkyl, cycloalkenyl, or multicyclic alkaryl, each of which is
optionally substituted one or more times independently by alkyl,
halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino,
dialkylamino, carboxy, or alkoxycarbonyl, or aryl, heteroaryl,
aroyl, heteroaroyl, aryloxy, heteroaryloxy, heterocyclyl,
heterocyclenyl, cycloalkyl, cycloalkenyl, or multicyclic alkaryl,
each of which is optionally substituted one or more times
independently by alkyl, haloalkyl, halo, alkoxy, haloalkoxy,
hydroxy, carboxy, alkoxycarbonyl, Y.sup.1Y.sup.2N--, or
Y.sup.1Y.sup.2N--SO.sub.2--, wherein the heterocyclyl,
heterocyclenyl, cycloalkyl, cycloalkenyl, or multicyclic alkaryl
moiety of R.sup.6 is also optionally substituted one or more times
independently by oxo; Y.sup.1 and Y.sup.2 are each independently:
hydrogen, alkylsulfonyl, aroyl, heteroaroyl, or alkyl optionally
substituted one or more times independently by hydroxy, carboxy,
halo, amino, alkylamino, dialkylamino, alkoxy, heterocyclyl, aryl
or heteroaryl, or Y.sup.1 and Y.sup.2 together with the nitrogen
atom to which they are attached form heterocyclyl; or a hydrate,
solvate or N-oxide thereof, or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1, wherein R.sup.1 is aryl or
heteroaryl, each of which is optionally substituted one or more
times independently by halo, (C.sub.1-C.sub.6)-alkyl, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, (C.sub.1-C.sub.4)-haloalkyl or
(C.sub.1-C.sub.4)-haloalkoxy, or a hydrate, solvate or N-oxide
thereof, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R.sup.1 is phenyl or
five or six membered heteroaryl, each of which is optionally
substituted one or more times independently by halo,
(C.sub.1-C.sub.6)-alkyl, hydroxy, or (C.sub.1-C.sub.6)-alkoxy, or a
hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
4. The compound according to claim 1, wherein R.sup.1 is phenyl,
pyridyl, pyrimidinyl, thiazolyl, or oxodiazolyl, each of which is
optionally substituted one or more times independently by halo,
(C.sub.1-C.sub.6)-alkyl, hydroxy, or (C.sub.1-C.sub.6)-alkoxy, or a
hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
5. The compound according to claim 1, wherein R.sup.1 is phenyl,
pyridyl or pyrimidyl, each of which is optionally substituted
independently at the ortho or meta position by halo,
(C.sub.1-C.sub.6)-alkyl, hydroxy, or (C.sub.1-C.sub.6)-alkoxy, or a
hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
6. The compound according to claim 1, wherein R.sup.1 is phenyl
optionally substituted independently at the ortho or meta position
by halo, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, wherein R.sup.1 is pyridyl,
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
8. The compound according to claim 1, wherein R.sup.2 is hydrogen,
methyl or trifluoromethyl, or a hydrate, solvate or N-oxide
thereof, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, wherein R.sup.2 is hydrogen,
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
10. The compound according to claim 1, wherein R.sup.2 is methyl,
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
11. The compound according to claim 1, wherein L.sup.1 is a bond,
--O--, --C(.dbd.O)--, or --NH--C(.dbd.O)--, or a hydrate, solvate
or N-oxide thereof, or a pharmaceutically acceptable salt
thereof.
12. The compound according to claim 1, wherein L.sup.1 is a bond,
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
13. The compound according to claim 1, wherein: R.sup.3 and R.sup.4
together with the nitrogen atom to which they are attached form
heterocyclyl, heterocyclenyl, arylheterocyclyl, or heteroaryl, each
of which is optionally substituted one or more times independently
by R.sup.6; R.sup.6 is alkoxy, hydroxyl, cycloalkyl, carboxy,
cycloalkyl, halo, cyano, alkylsulfonyl, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2N--SO.sub.2--, alkyl optionally substituted one or
more times independently by acyloxy, hydroxy, alkoxycarbonyl,
alkoxy, carboxy, aryl, halo, alkylsulfonyl, cyano,
Y.sup.1Y.sup.2N--, or Y.sup.1Y.sup.2N--C(.dbd.O)--, acyl or aryl,
each of which is optionally substituted one or more times
independently by halo, alkoxycarbonyl optionally substituted one or
more times independently by aryl, heteroaroyl optionally
substituted one or more times independently by alkyl, heterocyclyl
optionally substituted one or more times by oxo, or aryloxy
optionally substituted one or more times independently by
haloalkyl; and Y.sup.1 and Y.sup.2 are each independently hydrogen,
alkylsulfonyl, aroyl, or alkyl optionally substituted by
morpholinyl, or Y.sup.1 and Y.sup.2 together with the nitrogen atom
to which they are attached form morpholinyl; or a hydrate, solvate
or N-oxide thereof, or a pharmaceutically acceptable salt
thereof.
14. The compound according to claim 1, wherein: R.sup.3 and R.sup.4
together with the nitrogen atom to which they are attached form
[1,2,4]triazolyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridyl,
pyrrolo[3,2-b]pyridyl, or pyrrolo[2,3-c]pyridyl, each of which is
optionally substituted one or more times independently by R.sup.6;
R.sup.6 is alkoxy, carboxy, cycloalkyl, halo, cyano, alkylsulfonyl,
Y.sup.1Y.sup.2N--SO.sub.2--, alkyl optionally substituted one or
more times independently by Y.sup.1Y.sup.2N--C(.dbd.O)--, hydroxy,
alkoxycarbonyl, alkoxy, carboxy, aryl, halo, heterocyclyl,
cycloalkyl, alkylsulfonyl, cyano, heterocyclylcarbonyl, acyl or
aryl, each of which is optionally substituted one or more times
independently by halo, alkoxycarbonyl optionally substituted one or
more times independently by aryl, heteroaroyl optionally
substituted one or more times independently by alkyl, heterocyclyl
optionally substituted one or more times by oxo, or aryloxy
optionally substituted one or more times independently by
haloalkyl; and Y.sup.1 and Y.sup.2 are each independently hydrogen,
or alkyl optionally substituted by morpholinyl, or Y.sup.1 and
Y.sup.2 together with the nitrogen atom to which they are attached
form morpholinyl; or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
15. The compound according to claim 1, wherein: R.sup.3 and R.sup.4
together with the nitrogen atom to which they are attached form
imidazolidinyl, [1,2,4]thiazinanyl, piperazinyl, morpholinyl,
pyrrolidinyl, 1,2,3,4-tetrahydro-pyrimidinyl, piperidinyl,
oxazolidinyl, 2,3-dihydro-indolyl, octahydro-cyclopenta[c]pyrrolyl,
or 3,4-dihydro-benzo[1,4]oxazine, each of which is optionally
substituted one or more times independently by R.sup.6; R.sup.6 is
oxo, alkoxy, carboxy, cycloalkyl, halo, cyano, alkylsulfonyl,
Y.sup.1Y.sup.2N--SO.sub.2--, alkyl optionally substituted one or
more times independently by hydroxy, alkoxycarbonyl, alkoxy,
carboxy, aryl, halo, heterocyclyl, cycloalkyl, alkylsulfonyl,
cyano, heterocyclylcarbonyl, acyl or aryl, each of which is
optionally substituted one or more times independently by halo,
alkoxycarbonyl optionally substituted one or more times
independently by aryl, heteroaroyl optionally substituted one or
more times independently by alkyl, heterocyclyl optionally
substituted one or more times by oxo, or aryloxy optionally
substituted one or more times independently by haloalkyl; and
Y.sup.1 and Y.sup.2 are each independently hydrogen, or alkyl
optionally substituted by morpholinyl, or Y.sup.1 and Y.sup.2
together with the nitrogen atom to which they are attached form
morpholinyl; or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
16. The compound according to claim 1, wherein: R.sup.3 and R.sup.4
together with the nitrogen atom to which they are attached form
indolyl, optionally substituted one or more times independently by
R.sup.6; R.sup.6 is Y.sup.1Y.sup.2N--SO.sub.2--, alkoxycarbonyl,
carboxyalkyl, cyano, halo, alkylsulfonyl, alkoxy, or acyl
optionally substituted one or more times independently by halo; and
Y.sup.1 and Y.sup.2 are each independently hydrogen, or alkyl
optionally substituted by morpholinyl, or Y.sup.1 and Y.sup.2
together with the nitrogen atom to which they are attached form
morpholinyl; or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
17. The compound according to claim 1, wherein: R.sup.5 is phenyl,
pyridyl, or benzo[1,3]dioxolyl, each of which is optionally
substituted one or more times independently by R.sup.6; R.sup.6 is
Y.sup.1Y.sup.2N--SO.sub.2--, hydroxy, alkoxy, halo, alkyl, or
haloalkyl; and Y.sup.1 and Y.sup.2 are each independently hydrogen
or alkyl, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
18. The compound according to claim 1, which is
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide,
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dimethyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-chloro-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-bromo-indol-1-yl)-amide,
3-Oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid benzyl ester, 2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoro-indol-1-yl)amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide,
2-(3-Fluorophenyl)pyrimidine-5-carboxylicacid-[5-fluoro-3-(morpholine-4-s-
ulfonyl)indol-1-yl]amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(morpholine-4-sulfonyl) indol-1-yl]amide,
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-sulfamoylindol-1-yl)amide,
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide,
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide,
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide,
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide,
2-(Pyridin-2-yl)-pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide,
2-(Pyridin-2-yl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide, 2-Phenyl-pyrimidine-5-carboxylic
acid
[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyano-5-fluoro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid [1,2,4]triazol-4-ylamide,
2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-ylamide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-fluoro-phenyl)-hydrazide, 2-Phenyl-pyrimidine-5-carboxylic
acid N'-ethyl-N'-tolyl-hydrazide, 2-Phenyl-pyrimidine-5-carboxylic
acid (3-oxo-morpholin-4-yl)-amide,
2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, 2-Benzoyl-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, 2-Benzoyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[5-trifluoromethyl-pyridin-2-yl]-hydrazide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[4-trifluoromethyl-pyridin-2-yl]-hydrazide,
2-Phenyl-pyrimidine-5-carboxylic acid N'-pyridin-2-yl-hydrazide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-chloro-phenyl)-hydrazide, 2-Phenyl-pyrimidine-5-carboxylic
acid N'-(2-oxo-piperidin-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-cyclohexyl-N'-methyl-hydrazide,
2-Phenoxy-pyrimidine-5-carboxylic acid N'-morpholin-4-yl-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
3-{2,4-Dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-
-pyrimidin-5-yl}-propionic acid methyl ester,
3-{2,4-Dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-
-pyrimidin-5-yl}-propionic acid, 2-Phenyl-pyrimidine-5-carboxylic
acid (4-methyl-piperazin-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide,
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
((s)-2-methoxymethyl)-pyrrolidin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
((R)-2-methoxymethyl)-pyrrolidin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid pyrrol-1-ylamide,
2-Phenyl-pyrimidine-5-carboxylic acid
(5-morpholin-4-ylmethyl-2-oxo-oxazolidin-3-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(2-oxo-oxazolidin-3-yl)-amide,
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl]-amide,
[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl
ester, 2-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide,
4-[3-(4-Morpholino)propyl]-1-(2-phenyl-pyrimidine-5-carbonyl)-3-thiosemic-
arbazide, 2-Phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide,
{4-[2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-acetic
acid methyl ester, 2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyanomethyl-piperazin-1-yl)-amide, Acetic acid
2-{4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-ethyl
ester, 2-Phenyl-pyrimidine-5-carboxylic acid
(4-acetyl-piperazin-1-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic
acid [4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-methoxy-ethyl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide, 2-Phenyl-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide, 2-Phenyl-pyrimidine-5-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide,
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic
acid pyrrolidin-1-yl-amide, 2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-piperadin-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-pyridin-2-yl-hydrazide,
2-Phenyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid indol-1-yl-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid indol-1-yl-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
indol-1-ylamide, 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic
acid (2,3-dihydro-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
indol-1-ylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methanesulfonyl-indol-1-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide,
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl-4-methyl)-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, 2-Pyridin-2-yl-pyrimidine-5-carboxylic
acid (5-fluoro-indol-1-yl)-amide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridine-1-ylamide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide,
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-cyano-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(4-cyano-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[4-(1H-tetrazol-5-yl)-indol-1-yl]-amide,
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid methyl ester,
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyanomethyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(1H-tetrazol-5-ylmethyl)-indol-1-yl]-amide,
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazinecarboxamide,
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide,
2-Phenyl-pyrimidine-5-carboxylic acid
(2,4-dioxo-imidazolidin-1-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid N'-phenyl-hydrazide,
Pyridine-2-carboxylic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide,
4-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-benzenesulfonamide,
3-Hydroxy-benzoic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide,
Benzo[1,3]dioxo-5-carboxylic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide, 3,4-Dimethoxy-benzoic
acid N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide,
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-phenyl-hydrazide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-indol-1-yl)-amide,
2-(3-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(2-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(4-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(3-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(2-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
2-(4-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-Thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
[2,2']Bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylicacid(3-chloro-5-fluor-
o-indol-1-yl)-amide,
5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1-
H-indole-3-carboxylic acid amide,
2-{5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl}-2-methyl-propionic acid,
2-(5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino-
}-1H-indol-3-yl)-2-methyl-propionic acid,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-formyl-indol-1-yl)-amide,
5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-ind-
ole-3-carboxylic acid,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-hydroxymethyl-indol-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
N',N'-diphenyl-hydrazide
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(7-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-3-methyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3c]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-5-trifluoromethyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3c]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-nitro-indol-1-yl)-amide,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-(dimethanesulfonyl)-amino-indol-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-benzoylamino-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-indol-1-yl]-amide,
2-Pyridin-2-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide,
2-Pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxyl-indol-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(1-oxy-pyridin-2-yl)-pyrimidin-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Difluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, or
2-(3-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1, which is:
2-Phenyl-pyrimidine-5-carboxylic acid
(4-benzyl-piperazin-1-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic
acid piperazin-1-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid
(4-methanesulfonyl-piperazin-1-yl)-amide,
2-(2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-2-carbonyl)-piperazin-1-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-4-carbonyl)-piperazin-1-yl]-amide,
4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid tert-butyl ester, 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid
indol-1-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid
(4-methoxy-piperidin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide,
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-3-(2-morph-
olin-4-yl-ethyl)-1H-indole-6-carboxylic acid methyl ester,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide,
N-methyl-N-(5-fluoro)-indol-3-ylsulfonyl
N'-[2-(3-fluoro)-phenyl-pyrimidine-5-carbonyl]-hydrazide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(4-Methyl-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-3-oxo-2,3-dihydro-indazol-1-yl)amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid(5-fluoro-indol-1-yl)amide)amide,
6-(4-Chloro-thiazol-2-yl)-2-methyl-N-pyrrolo[2,3-c]pyridin-1-yl-nicotinam-
ide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid(5-methyl-4-oxo-4,5-dihydro-pyrrolo[3,2-c]pyridin-1-yl)amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-2,2-diuoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoro methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-difluoromethyl -pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro
methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[3,2-b]pyridin-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide,
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, or
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound according
to claim 1, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
21. A method for treating an allergic or inflammatory disorder in a
patient in need thereof, comprising administering to the patient a
pharmaceutically effective amount of the compound according to
claim 1, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
22. The method according to claim 21, wherein the allergic or
inflammatory disorder is allergic rhinitis.
23. The method according to claim 21, wherein the allergic or
inflammatory disorder is asthma.
24. The method according to claim 21, wherein the allergic or
inflammatory disorder is chronic obstructive pulmonary disease.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to pyrimidine hydrazide
compounds, their preparation, pharmaceutical compositions
containing these compounds, and their pharmaceutical use in the
treatment of disease states capable of being modulated by the
inhibition of the prostaglandin D synthase.
BACKGROUND OF THE INVENTION
[0002] Allergic rhinitis, the most common atopic disease, has an
estimated prevalence ranging from about 5 to about 22 percent of
the general human population and is characterized by the symptoms
of sneezing, nasal discharge, and nasal congestion. These symptoms
are believed to be triggered by multiple mediators released from
mast cells and other inflammatory cells. Current therapies, such as
antihistamines, deal effectively with the sneezing and nasal
discharge, but have little effect on congestion, which is a key
symptom affecting the quality of life of patients.
[0003] Local allergen challenge in patients with allergic rhinitis,
bronchial asthma, allergic conjunctivitis and atopic dermatitis has
been shown to result in rapid elevation of prostaglandin D2
"(PGD2)" levels in nasal and bronchial lavage fluids, tears and
skin chamber fluids. PGD2 has many inflammatory actions, such as
increasing vascular permeability in the conjunctiva and skin,
increasing nasal airway resistance, airway narrowing and eosinophil
infiltration into the conjunctiva and trachea. PGD2 is the major
cyclooxygenase product of arachidonic acid produced from mast cells
on immunological challenge [Lewis, R A, Soter N A, Diamond P T,
Austen K F, Oates J A, Roberts L J II, Prostaglandin D2 generation
after activation of rat and human mast cells with anti-IgE, J.
Immunol. 129, 1627-1631, 1982]. Activated mast cells, a major
source of PGD2, are one of the key players in driving the allergic
response in conditions such as asthma, allergic rhinitis, allergic
conjunctivitis, allergic dermatitis and other diseases [Brightling
C E, Bradding P, Pavord I D, Wardlaw A J, New Insights into the
role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556,
2003].
[0004] In the presence of sulfhydryl compounds, PGD2 is formed by
the isomerization of PGH2, a common precursor of prostanoids, by
catalytic action of prostaglandin D synthase "(PGDS)". There are
two isoforms of the PGDS enzyme: L-PGDS; and H-PGDS. H-PGDS is a
cytosolic enzyme, which is distributed in the peripheral tissues,
and which is localized in the antigen-presenting cells, mast cells,
megakaryocytes, and Th2 lymphocytes. The action of the product PGD2
is mediated by G-protein coupled receptors: D prostaglandin "(DP)"
and crTH2. See (1) Prostaglandin D Synthase: Structure and
Function. T. Urade and O. Hayaishi, Vitamin and Hormones, 2000, 58,
89-120, (2) J. J. Murray, N. Engl J. Med., 1986 Sep. 25;
315(13):800, and (3) Urade et. al, J. Immunology 168: 443-449,
2002.
[0005] We believe that inhibiting the formation of PGD2 should have
an effect on nasal congestion and, therefore, be of therapeutic
benefit in allergic rhinitis. In addition, we believe that a PGDS
inhibitor should be of therapeutic benefit in a number of other
indications such as bronchial asthma.
[0006] PGDS inhibitors have been reported. The compound, HQL-79, is
reported to be a weak PGDS inhibitor, and is antiasthmatic in
guinea pig and rat models (Matsusshita, et al., Jpn. J. Pharamcol.
78: 11, 1998). The compound Tranilast is described as a PGDS
inhibitor. (Inhibitory Effect of Tranilast on Prostaglandin D
Synthesase. K. Ikai, M. Jihara, K. Fujii, and Y. Urade. Biochemical
Pharmacology, 1989, 28, 2773-2676).
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a compound of formula
(I):
##STR00002##
wherein: [0008] R.sup.1 is (C.sub.1-C.sub.6)-alkyl optionally
substituted one or more times independently by halo, hydroxy,
(C.sub.1-C.sub.6)-alkoxy, or (C.sub.1-C.sub.4)-haloalkoxy, or
[0009] (C.sub.3-C.sub.6)-cycloalkyl, aryl or heteroaryl, each of
which is optionally substituted one or more times independently by
halo, (C.sub.1-C.sub.6)-alkyl, hydroxy, (C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-haloalkyl or (C.sub.1-C.sub.4)-haloalkoxy; [0010]
R.sup.2 is hydrogen or (C.sub.1-C.sub.4)-alkyl optionally
substituted one or more times by halo; [0011] R.sup.3 is hydrogen,
alkyl, aryl or heteroaryl, [0012] R.sup.4 is hydrogen, cycloalkyl,
aryl, heteroaryl, heterocyclyl, arylsulfonyl, heteroarylsulfonyl,
--C(.dbd.O)--NY.sup.1Y.sup.2, --C(.dbd.S)--NY.sup.1Y.sup.2,
R.sup.5, --C(.dbd.O)--R.sup.5 or --C(.dbd.S)--R.sup.5, wherein the
aryl, heteroaryl or heterocyclyl moiety is optionally substituted
one or more times independently by R.sup.6, or [0013] R.sup.3 and
R.sup.4 together with the nitrogen atom to which they are attached
form heterocyclyl, heterocyclenyl, heteroaryl, arylheterocyclyl,
arylheterocylenyl, heteroarylheterocyclyl,
heteroarylheterocyclenyl, heterocyclylheteroaryl or
heterocyclenylheteroaryl, each of which is optionally substituted
one or more times independently by R.sup.6; [0014] R.sup.5 is
cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,
heterocyclenyl, or multicyclic alkaryl, each of which is optionally
substituted one or more times independently by R.sup.6; [0015]
L.sup.1 is a bond, --O--, --C(.dbd.O)--, --NH--C(.dbd.O)--, or
(C.sub.1-C.sub.2)-alkylene optionally substituted one or more times
by halo; [0016] R.sup.6 is cyano, nitro, halo, hydroxy, carboxy,
Y.sup.1Y.sup.2N--, Y.sup.1Y.sup.2N--C(.dbd.O)--,
Y.sup.1Y.sup.2N--SO.sub.2--, [0017] acyl, acyloxy, alkyl, alkenyl,
alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or
alkylsulfonyl, each of which is optionally substituted one or more
times independently by: [0018] acyloxy, halo, alkoxy, haloalkoxy,
hydroxy, carboxy, alkoxycarbonyl, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2N--C(.dbd.O)--, Y.sup.1Y.sup.2N--SO.sub.2--, [0019]
aryl, aryloxy, aroyl, heteroaryl, heteroaryloxy, heteroaroyl,
heterocyclyl, heterocyclenyl, cycloalkyl, cycloalkenyl, or
multicyclic alkaryl, each of which is optionally substituted one or
more times independently by alkyl, halo, haloalkyl, alkoxy,
haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or
alkoxycarbonyl, or [0020] aryl, heteroaryl, aroyl, heteroaroyl,
aryloxy, heteroaryloxy, heterocyclyl, heterocyclenyl, cycloalkyl,
cycloalkenyl, or multicyclic alkaryl, each of which is optionally
substituted one or more times independently by alkyl, haloalkyl,
halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl,
Y.sup.1Y.sup.2N--, or Y.sup.1Y.sup.2N--SO.sub.2--, [0021] wherein
the heterocyclyl, heterocyclenyl, cycloalkyl, cycloalkenyl, or
multicyclic alkaryl moiety of R.sup.6 is also optionally
substituted one or more times independently by oxo; [0022] Y.sup.1
and Y.sup.2 are each independently: [0023] hydrogen, alkylsulfonyl,
aroyl, heteroaroyl, or alkyl optionally substituted one or more
times independently by hydroxy, carboxy, halo, amino, alkylamino,
dialkylamino, alkoxy, heterocyclyl, aryl or heteroaryl, or [0024]
Y.sup.1 and Y.sup.2 together with the nitrogen atom to which they
are attached form heterocyclyl; or a hydrate, solvate or N-oxide
thereof, or a pharmaceutically acceptable salt thereof.
[0025] Another aspect of the present invention is a pharmaceutical
composition comprising a pharmaceutically effective amount of a
compound according to formula (I), or a hydrate, solvate or N-oxide
thereof, or a pharmaceutically acceptable salt thereof, in
admixture with a pharmaceutically acceptable carrier.
[0026] Another aspect of the present invention is directed to a
method of treating allergic and/or inflammatory disorders,
particularly disorders such as allergic rhinitis, asthma and/or
chronic obstructive pulmonary disease (COPD) in a patient in need
thereof by administering to the patient a compound according to
formula (I), or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0027] As used above, and throughout the description of the
invention, the following terms unless otherwise indicated, shall be
understood to have the following meanings:
[0028] "Acyl" means H--CO-- or (aliphatic or cyclyl)-CO--.
Particular acyl includes lower alkanoyl that contains a lower
alkyl. Exemplary acyl includes formyl, acetyl, propanoyl,
2-methylpropanoyl, butanoyl, palmitoyl, acryloyl, propynoyl, and
cyclohexylcarbonyl.
[0029] "Acyloxy" means acyl-O--.
[0030] "Alkenyl" means a straight or branched aliphatic hydrocarbon
group containing a carbon-carbon double bond and having 2 to about
15 carbon atoms. Particular alkenyl has 2 to about 12 carbon atoms.
More particular alkenyl has 2 to about 4 carbon atoms. Branched
means that one or more lower alkyl groups such as methyl, ethyl or
propyl are attached to a linear alkenyl chain. "Lower alkenyl"
means about 2 to about 4 carbon atoms in the chain that may be
straight or branched. Exemplary alkenyl includes ethenyl, propenyl,
n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl,
octenyl, cyclohexylbutenyl, and decenyl.
[0031] "Alkoxy" means alkyl-O--. Exemplary alkoxy includes methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy.
[0032] "Alkoxycarbonyl" means alkyl-O--CO--. Exemplary
alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, and
t-butyloxycarbonyl.
[0033] "Alkyl" means straight or branched aliphatic hydrocarbon
having 1 to about 20 carbon atoms. Particular alkyl has 1 to about
12 carbon atoms. More particular alkyl is lower alkyl. Branched
means that one or more lower alkyl groups such as methyl, ethyl or
propyl are attached to a linear alkyl chain. "Lower alkyl" means 1
to about 4 carbon atoms in a linear alkyl chain that may be
straight or branched.
[0034] "Alkylamino" means alkyl-NH--. Particular alkylamino is
(C.sub.1-C.sub.6)-alkylamino. Exemplary alkylamino includes
methylamino and ethylamino.
[0035] "Alkylsulfinyl" means alkyl-SO--. Particular alkylsulfonyl
is (C.sub.1-C.sub.6)-alkylsulfinyl. Exemplary alkylsulfinyl
includes CH.sub.3--SO--, and CH.sub.3CH.sub.2--SO--.
[0036] "Alkylsulfonyl" means alkyl-SO.sub.2--. Particular
alkylsulfonyl is (C.sub.1-C.sub.6)-alkylsulfonyl. Exemplary
alkylsulfonyl includes CH.sub.3--SO.sub.2--, and
CH.sub.3CH.sub.2--SO.sub.2--.
[0037] "Alkylthio" means an alkyl-S--. Exemplary alkylthio includes
CH.sub.3--S--.
[0038] "Alkynyl" means straight or branched aliphatic hydrocarbon
containing a carbon-carbon triple bond and having 2 to about 15
carbon atoms. Particular alkynyl has 2 to about 12 carbon atoms.
More particular alkynyl has 2 to about 6 carbon atoms. Branched
means that one or more lower alkyl such as methyl, ethyl or propyl
are attached to a linear alkynyl chain.
[0039] "Lower alkynyl" means 2 to about 4 carbon atoms in a linear
alkynyl chain that may be straight or branched. Exemplary alkynyl
includes ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl,
n-pentynyl, heptynyl, octynyl, and decynyl.
[0040] "Aroyl" means aryl-CO--. Exemplary aroyl includes benzoyl,
and 1- and 2-naphthoyl.
[0041] "Aryl" means an aromatic monocyclic or multicyclic ring
system of about 6 to about 14 carbon atoms. Particular aryl include
about 6 to about 10 carbon atoms. Exemplary aryl include phenyl and
naphthyl.
[0042] "Arylcycloalkenyl" means a fused aryl and cycloalkenyl.
Particular arylcycloalkenyl is one wherein the aryl thereof is
phenyl and the cycloalkenyl consists of about 5 to about 7 ring
atoms. An arylcycloalkenyl is bonded through any atom of the
cycloalkenyl moiety thereof capable of such bonding. Exemplary
arylcycloalkenyl includes 1,2-dihydronaphthylene and indene.
[0043] "Arylcycloalkyl" means a fused aryl and cycloalkyl.
Particular arylcycloalkyl is one wherein the aryl thereof is phenyl
and the cycloalkyl consists of about 5 to about 6 ring atoms. An
arylcycloalkyl is bonded through any atom of the cycloalkyl moiety
thereof capable of such bonding. Exemplary arylcycloalkyl includes
1,2,3,4-tetrahydro-naphthylene.
[0044] "Arylheterocyclenyl" means a fused aryl and heterocyclenyl.
Particular arylheterocyclenyl is one wherein the aryl thereof is
phenyl and the heterocyclenyl consists of about 5 to about 6 ring
atoms. An arylheterocyclenyl is bonded through any atom of the
heterocyclenyl thereof capable of such bonding. The designation of
the aza, oxa or thio as a prefix before the heterocyclenyl portion
of the arylheterocyclenyl defines that at least a nitrogen, oxygen
or sulfur atom is present, respectively, as a ring atom. The
nitrogen atom of an arylheterocyclenyl may be a basic nitrogen
atom. The nitrogen or sulfur atom of the heterocyclenyl portion of
the arylheterocyclenyl may also be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
arylheterocyclenyl includes 3H-indolinyl, 1H-2-oxoquinolyl,
2H-1-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl,
1,2-dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
[0045] "Arylheterocyclyl" means a fused aryl and heterocyclyl.
Particular heterocyclylaryl is one wherein the aryl thereof is
phenyl and the heterocyclyl consists of about 5 to about 6 ring
atoms. An arylheterocyclyl is bonded through any atom of the
heterocyclyl moiety thereof capable of such bonding. The
designation of the aza, oxa or thio as a prefix before heterocyclyl
portion of the arylheterocyclyl defines that at least a nitrogen,
oxygen or sulfur atom is present, respectively, as a ring atom. The
nitrogen atom of an arylheterocyclyl may be a basic nitrogen atom.
The nitrogen or sulfur atom of the heterocyclyl portion of the
arylheterocyclyl may also be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
arylheterocyclyl includes indolinyl,
1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline,
1H-2,3-dihydroisoindol-2-yl, 2,3-dihydrobenz[f]isoindol-2-yl, and
1,2,3,4-tetrahydrobenz[g]-isoquinolin-2-yl.
[0046] "Aryloxy" means an aryl-O--. Exemplary aryloxy includes
phenoxy and naphthoxy.
[0047] "Compounds of the present invention", and equivalent
expressions, are meant to embrace compounds of Formula (I) as
hereinbefore described, the hydrates, solvates and N-oxides
thereof, and the pharmaceutically acceptable salts thereof, where
the context so permits. Similarly, reference to intermediates,
whether or not they themselves are claimed, is meant to embrace
their salts, N-oxides and solvates, where the context so
permits.
[0048] "Cycloalkenyl" means a non-aromatic mono- or multicyclic
ring system of about 3 to about 10 carbon atoms, particularly of
about 5 to about 10 carbon atoms, and which contains at least one
carbon-carbon double bond. Particular rings of the ring system
include about 5 to about 6 ring atoms; and such particular ring
sizes are also referred to as "lower". Exemplary monocyclic
cycloalkenyl includes cyclopentenyl, cyclohexenyl, and
cycloheptenyl. An exemplary multicyclic cycloalkenyl is
norbornylenyl.
[0049] "Cycloalkenylaryl" means a fused aryl and cycloalkenyl.
Particular cycloalkenylaryl is one wherein the aryl thereof is
phenyl and the cycloalkenyl consists of about 5 to about 6 ring
atoms. A cycloalkenylaryl is bonded through any atom of the aryl
moiety thereof capable of such bonding. Exemplary cycloalkenylaryl
includes 1,2-dihydronaphthylene and indene.
[0050] "Cycloalkenylheteroaryl" means a fused heteroaryl and
cycloalkenyl. Particular cycloalkenylheteroaryl is one wherein the
heteroaryl thereof consists of about 5 to about 6 ring atoms and
the cycloalkenyl consists of about 5 to about 6 ring atoms. A
cycloalkenylheteroaryl is bonded through any atom of the heteroaryl
thereof capable of such bonding. The designation of the aza, oxa or
thio as a prefix before heteroaryl portion of the
cycloalkenylheteroaryl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. The nitrogen
atom of a cycloalkenylheteroaryl may be a basic nitrogen atom. The
nitrogen atom of the heteroaryl portion of the
cycloalkenylheteroaryl may also be optionally oxidized to the
corresponding N-oxide. Exemplary cycloalkenylheteroaryl includes
5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl,
5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl,
4,5-dihydro-1H-benzimidazolyl, and 4,5-di-hydrobenzoxazolyl.
[0051] "Cycloalkyl" means a non-aromatic mono- or multicyclic
saturated ring system of about 3 to about 10 carbon atoms,
particularly of about 5 to about 10 carbon atoms. Particular ring
systems include about 5 to about 7 ring atoms; and such particular
ring systems are also referred to as "lower". Exemplary monocyclic
cycloalkyl includes cyclopentyl, cyclohexyl, and cycloheptyl.
Exemplary multicyclic cycloalkyl includes 1-decalin, norbornyl, and
adamant-(1- or 2-)yl.
[0052] "Cycloalkylaryl" means a fused aryl and cycloalkyl.
Particular cycloalkylaryl is one wherein the aryl thereof is phenyl
and the cycloalkyl consists of about 5 to about 6 ring atoms. A
cycloalkylaryl is bonded through any atom of the cycloalkyl moiety
thereof capable of such bonding. Exemplary cycloalkylaryl includes
1,2,3,4-tetrahydro-naphthylene.
[0053] "Cycloalkylheteroaryl" means a fused heteroaryl and
cycloalkyl. Particular cycloalkylheteroaryl is one wherein the
heteroaryl thereof consists of about 5 to about 6 ring atoms and
the cycloalkyl consists of about 5 to about 6 ring atoms. A
cycloalkylheteroaryl is bonded through any atom of the heteroaryl
thereof capable of such bonding. The designation of the aza, oxa or
thio as a prefix before heteroaryl portion of the fused
cycloalkylheteroaryl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. The nitrogen
atom of a cycloalkylheteroaryl may be a basic nitrogen atom. The
nitrogen atom of the heteroaryl portion of the cycloalkylheteroaryl
may also be optionally oxidized to the corresponding N-oxide.
Exemplary cycloalkylheteroaryl includes
5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl,
5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl,
4,5,6,7-tetrahydro-1H-benzimidazolyl, and
4,5,6,7-tetrahydrobenzoxazolyl.
[0054] "Cyclyl" means cycloalkyl, cycloalkenyl, heterocyclyl or
heterocyclenyl.
[0055] "Dialkylamino" means (alkyl).sub.2-N--. Particular
dialkylamino is (C.sub.1-C.sub.6alkyl).sub.2-N--. Exemplary
dialkylamino groups include dimethylamino, diethylamino and
methylethylamino.
[0056] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo.
Particular halo or halogen is fluoro or chloro.
[0057] "Haloalkoxy" means alkoxy substituted by one to three halo
groups. Particular haloalkoxy are loweralkoxy substituted by one to
three halogens. Most particular haloalkoxy are loweralkoxy
substituted by one halogen.
[0058] "Haloalkyl" means alkyl substituted by one to three halo
groups. Particular haloalkyl are loweralkyl substituted by one to
three halogens. Most particular haloalkyl are loweralkyl
substituted by one halogen.
[0059] "Heteroaroyl" means heteroaryl-CO--. Exemplary heteroaroyl
includes thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, and
pyridinoyl.
[0060] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system of about 5 to about 14 carbon atoms, in which one or
more of the carbon atoms in the ring system is/are hetero
element(s) other than carbon, for example nitrogen, oxygen or
sulfur. Particular aromatic ring systems include about 5 to about
10 carbon atoms, and include 1 to 3 heteroatoms. More particular
ring sizes of rings of the ring system include about 5 to about 6
ring atoms. The designation of the aza, oxa or thio as a prefix
before heteroaryl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. A nitrogen
atom of a heteroaryl may be a basic nitrogen atom and may also be
optionally oxidized to the corresponding N-oxide. When a heteroaryl
is substituted by a hydroxy group, it also includes its
corresponding tautomer. Exemplary heteroaryl includes pyrazinyl,
thienyl, isothiazolyl, oxazolyl, pyrazolyl, furanyl, pyrrolyl,
1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl,
imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofuranyl,
azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindolyl,
1,2,4-triazinyl, benzothiazolyl, imidazolyl, indolyl, indolizinyl,
isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl,
pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl,
quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl,
and triazolyl.
[0061] "Heteroarylalkyl" means heteroaryl-alkyl-. Particular
heteroarylalkyl contains a (C.sub.1-C.sub.4)-alkyl moiety.
Exemplary heteroarylalkyl includes tetrazol-5-ylmethyl.
[0062] "Heteroarylcycloalkenyl" means a fused heteroaryl and
cycloalkenyl. Particular heteroarylcycloalkenyl is one wherein the
heteroaryl thereof consists of about 5 to about 6 ring atoms and
the cycloalkenyl consists of about 5 to about 6 ring atoms. A
heteroarylcycloalkenyl is bonded through any atom of the
cycloalkenyl thereof capable of such bonding. The designation of
the aza, oxa or thio as a prefix before heteroaryl portion of the
heteroarylcycloalkenyl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. The nitrogen
atom of a heteroarylcycloalkenyl may be a basic nitrogen atom. The
nitrogen atom of the heteroaryl portion of the
heteroarylcycloalkenyl may also be optionally oxidized to the
corresponding N-oxide. Exemplary heteroarylcycloalkenyl includes
5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl,
5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl,
4,5-dihydro-1H-benzimidazolyl, and 4,5-di-hydrobenzoxazolyl.
[0063] "Heteroarylcycloalkyl" means a fused heteroaryl and
cycloalkyl. Particular heteroarylcycloalkyl is one wherein the
heteroaryl thereof consists of about 5 to about 6 ring atoms and
the cycloalkyl consists of about 5 to about 6 ring atoms. A
heteroarylcycloalkyl is bonded through any atom of the cycloalkyl
thereof capable of such bonding. The designation of the aza, oxa or
thio as a prefix before heteroaryl portion of the fused
heteroarylcycloalkyl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. The nitrogen
atom of a heteroarylcycloalkyl may be a basic nitrogen atom. The
nitrogen atom of the heteroaryl portion of the heteroarylcycloalkyl
may also be optionally oxidized to the corresponding N-oxide.
Exemplary heteroarylcycloalkyl includes
5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl,
5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl,
4,5,6,7-tetrahydro-1H-benzimidazolyl, and
4,5,6,7-tetrahydrobenzoxazolyl "Heteroarylheterocyclenyl" means a
fused heteroaryl and heterocyclenyl. Particular
heteroarylheterocyclenyl is one wherein the heteroaryl thereof
consists of about 5 to about 6 ring atoms and the heterocyclenyl
consists of about 5 to about 6 ring atoms. A
heteroarylheterocyclenyl is bonded through any atom of the
heterocyclenyl thereof capable of such bonding. The designation of
the aza, oxa or thio as a prefix before the heteroaryl or
heterocyclenyl portion of the heteroarylheterocyclenyl defines that
at least a nitrogen, oxygen or sulfur atom is present,
respectively, as a ring atom. The nitrogen atom of a
heteroarylazaheterocyclenyl may be a basic nitrogen atom. The
nitrogen or sulfur atom of the heteroaryl or heterocyclenyl portion
of the heteroarylheterocyclenyl may also be optionally oxidized to
the corresponding N-oxide, S-- oxide or S,S-dioxide. Exemplary
heteroarylheterocyclenyl includes 7,8-dihydro[1,7]naphthyridinyl,
1,2-dihydro[2,7]-naphthyridinyl,
6,7-dihydro-3H-imidazo[4,5-c]pyridyl,
1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl,
1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl, and
1,2-dihydro-2,6-naphthyridinyl.
[0064] "Heteroarylheterocyclyl" means a fused heteroaryl and
heterocyclyl. Particular heteroarylheterocyclyl is one wherein the
heteroaryl thereof consists of about 5 to about 6 ring atoms and
the heterocyclyl consists of about 5 to about 6 ring atoms. A
heteroarylheterocyclyl is bonded through any atom of the
heterocyclyl thereof capable of such bonding. The designation of
the aza, oxa or thio as a prefix before the heteroaryl or
heterocyclyl portion of the fused heteroarylheterocyclyl defines
that at least a nitrogen, oxygen or sulfur atom is present,
respectively, as a ring atom. The nitrogen atom of a fused
heteroarylheterocyclyl may be a basic nitrogen atom. The nitrogen
or sulfur atom of the heteroaryl or heterocyclyl portion of the
heteroarylheterocyclyl may also be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
heteroarylheterocyclyl includes
2,3-dihydro-1H-pyrrol[3,4-b]quinolin-2-yl,
1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl,
1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl,
1,2,3,4-tetra-hydro-9H-pyrido[3,4-b]indol-2-yl,
1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl,
2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl,
1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl,
1H-2,3,4,5-tetra-hydroazepino[4,3-b]indol-3-yl,
1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl,
5,6,7,8-tetra-hydro[1,7]naphthyridyl,
1,2,3,4-tetrhydro[2,7]naphthyridyl,
2,3-dihydro[1,4]dioxino[2,3-b]pyridyl,
2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl,
3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl,
6,7-dihydro[5,8]diazanaphthalenyl,
1,2,3,4-tetrahydro[1,5]-naphthyridinyl,
1,2,3,4-tetrahydro[1,6]naphthyridinyl,
1,2,3,4-tetrahydro[1,7]naphthyridinyl,
1,2,3,4-tetrahydro[1,8]naphthyridinyl, and
1,2,3,4-tetra-hydro[2,6]naphthyridinyl.
[0065] "Heteroaryloxy" means heteroaryl-O--. Exemplary
heteroaryloxy includes pyridyloxy.
[0066] "Heterocyclenyl" means a non-aromatic monocyclic or
multicyclic hydrocarbon ring system of about 3 to about 10 carbon
atoms, in which one or more of the carbon atoms in the ring system
is/are hetero element(s) other than carbon, for example nitrogen,
oxygen or sulfur atoms, and which contains at least one
carbon-carbon double bond or carbon-nitrogen double bond. A
particular non-aromatic ring system includes about 5 to about 10
carbon atoms, and 1 to 3 heteroatoms. More particular ring sizes of
rings of the ring system include about 5 to about 6 ring atoms; and
such particular ring sizes are also referred to as "lower". The
designation of the aza, oxa or thio as a prefix before
heterocyclenyl defines that at least a nitrogen, oxygen or sulfur
atom is present, respectively, as a ring atom. The nitrogen atom of
a heterocyclenyl may be a basic nitrogen atom. The nitrogen or
sulfur atom of the heterocyclenyl may also be optionally oxidized
to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
monocyclic azaheterocyclenyl includes
1,2,3,4-tetrahydrohydropyridyl, 1,2-dihydropyridyl,
1,4-dihydropyridyl, 1,2,3,6-tetra-hydropyridyl,
1,4,5,6-tetrahydro-pyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,
2-imidazolinyl, and 2-pyrazolinyl. Exemplary oxaheterocyclenyl
includes 3,4-dihydro-2H-pyran, dihydrofuranyl, and
fluorodihydro-furanyl. An exemplary multicyclic oxaheterocyclenyl
is 7-oxabicyclo[2.2.1]heptenyl. Exemplary monocyclic
thioheterocyclenyl includes dihydrothiophenyl and
dihydrothiopyranyl.
[0067] "Heterocyclenylaryl" means a fused aryl and heterocyclenyl.
Particular heterocyclenylaryl is one wherein the aryl thereof is
phenyl and the heterocyclenyl consists of about 5 to about 6 ring
atoms. A heterocyclenylaryl is bonded through any atom of the aryl
thereof capable of such bonding. The designation of the aza, oxa or
thio as a prefix before heterocyclenyl portion of the fused
heterocyclenylaryl defines that at least a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. The nitrogen
atom of a heterocyclenylaryl may be a basic nitrogen atom. The
nitrogen or sulfur atom of the heterocyclenyl portion of the
heterocyclenylaryl may also be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
heterocyclenylaryl include 3H-indolinyl, 1H-2-oxoquinolyl,
2H-1-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl,
1,2-dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
[0068] "Heterocyclenylheteroaryl" means a fused heteroaryl and
heterocyclenyl. Particular heterocyclenylheteroaryl is one wherein
the heteroaryl thereof consists of about 5 to about 6 ring atoms
and the heterocyclenyl consists of about 5 to about 6 ring atoms. A
heterocyclenylheteroaryl is bonded through any atom of the
heteroaryl thereof capable of such bonding. The designation of the
aza, oxa or thio as a prefix before the heteroaryl or
heterocyclenyl portion of the heterocyclenylheteroaryl define that
at least a nitrogen, oxygen or sulfur atom is present,
respectively, as a ring atom. The nitrogen atom of an
azaheterocyclenylheteroaryl may be a basic nitrogen atom. The
nitrogen or sulfur atom of the heteroaryl or heterocyclenyl portion
of the heterocyclenylheteroaryl may also be optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
heterocyclenylheteroaryl includes 7,8-dihydro[1,7]naphthyridinyl,
1,2-dihydro[2,7]-naphthyridinyl,
6,7-dihydro-3H-imidazo[4,5-c]pyridyl,
1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl,
1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl and
1,2-dihydro-2,6-naphthyridinyl.
[0069] "Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system of about 3 to about 10 carbon atoms, in
which one or more of the atoms in the ring system is/are hetero
element(s) other than carbon, for example nitrogen, oxygen or
sulfur. A particular ring system contains about 5 to about 10
carbon atoms, and from 1 to 3 heteroatoms. Particular ring sizes of
the ring system include about 5 to about 6 ring atoms; and such
particular ring sizes are also referred to as "lower". The
designation of the aza, oxa or thio as a prefix before heterocyclyl
define that at least a nitrogen, oxygen or sulfur atom is present
respectively as a ring atom. The nitrogen atom of a heterocyclyl
may be a basic nitrogen atom. The nitrogen or sulfur atom of the
heterocyclyl may also be optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. Exemplary monocyclic heterocyclyl
includes piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,
THFyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
[0070] "Heterocyclylaryl" means a fused aryl and heterocyclyl.
Particular heterocyclylaryl is one wherein the aryl thereof is
phenyl and the heterocyclyl consists of about 5 to about 6 ring
atoms. A heterocyclylaryl is bonded through any atom of the aryl
moiety thereof capable of such bonding. The designation of the aza,
oxa or thio as a prefix before heterocyclyl portion of the
heterocyclylaryl defines that at least a nitrogen, oxygen or sulfur
atom is present, respectively, as a ring atom. The nitrogen atom of
a heterocyclylaryl may be a basic nitrogen atom. The nitrogen or
sulfur atom of the heterocyclyl portion of the heterocyclylaryl may
also be optionally oxidized to the corresponding N-oxide, S-oxide
or S,S-dioxide. Exemplary heterocyclylaryl includes indolinyl,
1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline,
1H-2,3-dihydroisoindol-2-yl, and 2,3-dihydrobenz[f]isoindol-2-yl,
and 1,2,3,4-tetrahydrobenz[g]-isoquinolin-2-yl.
[0071] "Heterocyclylheteroaryl" means a fused heteroaryl and
heterocyclyl. Particular heterocyclylheteroaryl is one wherein the
heteoraryl thereof consists of about 5 to about 6 ring atoms and
the heterocyclyl consists of about 5 to about 6 ring atoms. A
heterocyclylheteroaryl is bonded through any atom of the heteroaryl
thereof capable of such bonding. The designation of the aza, oxa or
thio as a prefix before the heteroaryl or heterocyclyl portion of
the heterocyclylheteroaryl defines that at least a nitrogen, oxygen
or sulfur atom is present, respectively, as a ring atom. The
nitrogen atom of a heterocyclylheteroaryl may be a basic nitrogen
atom. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl
portion of the heterocyclylheteroaryl may also be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Exemplary heterocyclylheteroaryl includes
2,3-dihydro-1H-pyrrol[3,4-b]quinolin-2-yl,
1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl,
1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl,
1,2,3,4-tetra-hydro-9H-pyrido[3,4-b]indol-2-yl,
1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl,
2,3-dihydro-1H-pyrrolo[3,4-b]indol-2-yl,
1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl,
1H-2,3,4,5-tetra-hydroazepino[4,3-b]indol-3-yl,
1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2-yl,
5,6,7,8-tetra-hydro[1,7]naphthyridyl,
1,2,3,4-tetrhydro[2,7]naphthyridyl,
2,3-dihydro[1,4]dioxino[2,3-b]pyridyl,
2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl,
3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl,
6,7-dihydro[5,8]diazanaphthalenyl,
1,2,3,4-tetrahydro[1,5]-naphthyridinyl,
1,2,3,4-tetrahydro[1,6]naphthyridinyl,
1,2,3,4-tetrahydro[1,7]naphthyridinyl,
1,2,3,4-tetrahydro[1,8]naphthyridinyl, and
1,2,3,4-tetra-hydro[2,6]naphthyridinyl.
[0072] "Multicyclic alkaryl" means a multicyclic ring system
including at least one aromatic ring fused to at least one
non-aromatic ring that may be saturated or unsaturated, and may
also contain in the ring system one or more heteroatoms, such as
nitrogen, oxygen or sulfur. Exemplary multicyclic alkaryl includes
arylcycloalkenyl, arylcycloalkyl, arylheterocyclenyl,
arylheterocyclyl, cycloalkenylaryl, cycloalkylaryl,
cycloalkenylheteroaryl, cycloalkylheteroaryl,
heteroarylcycloalkenyl, heteroarylcycloalkyl,
heteroarylheterocyclenyl, heteroarylheterocyclyl,
heterocyclenylaryl, heterocyclenylheteroaryl, heterocyclylaryl, and
heterocyclylheteroaryl. Particular multicyclic alkaryl groups are
bicyclic rings that include one aromatic ring fused to one
non-aromatic ring and that also may contain in the ring system one
or more heteroatoms, such as nitrogen, oxygen or sulfur.
[0073] "Patient" includes human and other mammals.
[0074] "Pharmaceutically acceptable salts" refers to the non-toxic,
inorganic and organic acid addition salts, and base addition salts,
of compounds of the present invention. These salts may be prepared
in situ during the final isolation and purification of the
compounds or by separately reacting the purified compound in its
free base form with a suitable organic or inorganic acid and
isolating the salt thus formed. In some cases, the compounds
themselves are capable of self-protonating basic sites on the
molecule and forming an internal amphoteric salt.
[0075] Exemplary acid addition salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate, sulfamates, malonates, salicylates, propionates,
methylene-bis-.beta.-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,
benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and
laurylsulfonate salts. See, for example S. M. Berge, et al.,
"Pharmaceutical Salts," J. Pharm. Sci. 66, 1-19 (1977) that is
incorporated herein by reference. Base addition salts can also be
prepared by separately reacting the purified compound in its acid
form with a suitable organic or inorganic base and isolating the
salt thus formed. Base addition salts include pharmaceutically
acceptable metal and amine salts. Suitable metal salts include the
sodium, potassium, calcium, barium, zinc, magnesium, and aluminum
salts. A particular base addition salt is sodium salt or potassium
salt. Suitable inorganic base addition salts are prepared from
metal bases which include sodium hydride, sodium hydroxide,
potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium
hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine
base addition salts are prepared from amines which have sufficient
basicity to form a stable salt, and particularly include those
amines which are frequently used in medicinal chemistry because of
their low toxicity and acceptability for medical use. Exemplary
amin includes ammonia, ethylenediamine, N-methyl-glucamine, lysine,
arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,
tetramethylammonium hydroxide, triethylamine, dibenzylamine,
ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine,
tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g.,
lysine and arginine, and dicyclohexylamine.
[0076] "Solvate" means a physical association of a compound of the
present invention with one or more solvent molecules. This physical
association includes hydrogen bonding. In certain instances, the
solvate will be capable of isolation, for example when one or more
solvent molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
insoluble solvates. Particular solvates include hydrates,
ethanolates, and methanolates.
[0077] "Substituted one or more times independently" means
substituted one or more times by same or different substituent
groups, particularly substituted one, two or three times by same or
different substituent groups.
PARTICULAR EMBODIMENTS OF THE INVENTION
[0078] One particular embodiment of the invention is a compound of
formula (I) wherein R.sup.1 is aryl or heteroaryl, each of which is
optionally substituted one or more times independently by halo,
(C.sub.1-C.sub.6)-alkyl, hydroxy, (C.sub.1-C.sub.6)-alkoxy,
(C.sub.1-C.sub.4)-haloalkyl or (C.sub.1-C.sub.4)-haloalkoxy, or a
hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
[0079] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.1 is phenyl or five or six membered
heteroaryl, each of which is optionally substituted one or more
times independently by halo, (C.sub.1-C.sub.6)-alkyl, hydroxy, or
(C.sub.1-C.sub.6)-alkoxy, or a hydrate, solvate or N-oxide thereof,
or a pharmaceutically acceptable salt thereof.
[0080] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.1 is phenyl, pyridyl, pyrimidinyl,
thiazolyl, or oxodiazolyl, each of which is optionally substituted
one or more times independently by halo, (C.sub.1-C.sub.6)-alkyl,
hydroxy, or (C.sub.1-C.sub.6)-alkoxy, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0081] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.1 is phenyl, pyridyl or pyrimidinyl,
each of which is optionally substituted independently at the ortho
or meta position by halo, (C.sub.1-C.sub.6)-alkyl, hydroxy, or
(C.sub.1-C.sub.6)-alkoxy, or a hydrate, solvate or N-oxide thereof,
or a pharmaceutically acceptable salt thereof.
[0082] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.1 is phenyl optionally substituted
independently at the ortho or meta position by halo, or a hydrate,
solvate or N-oxide thereof, or a pharmaceutically acceptable salt
thereof.
[0083] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.1 is pyridyl, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0084] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.2 is hydrogen, methyl or
trifluoromethyl, or a hydrate solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
[0085] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.2 is hydrogen, or a hydrate, solvate
or N-oxide thereof, or a pharmaceutically acceptable salt
thereof.
[0086] Another particular embodiment of the invention is a compound
of formula (I) wherein R.sup.2 is methyl, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0087] Another particular embodiment of the invention is a compound
of formula (I) wherein L.sup.1 is a bond, --O--, --C(.dbd.O)--, or
--NH--C(.dbd.O)--, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
[0088] Another particular embodiment of the invention is a compound
of formula (I) wherein L.sup.1 is a bond, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0089] Another particular embodiment of the invention is a compound
of formula (I) wherein: [0090] R.sup.3 and R.sup.4 together with
the nitrogen atom to which they are attached form heterocyclyl,
heterocyclenyl, arylheterocyclyl, or heteroaryl, each of which is
optionally substituted one or more times independently by R.sup.6;
[0091] R.sup.6 is alkoxy, hydroxyl, cycloalkyl, carboxy,
cycloalkyl, halo, cyano, alkylsulfonyl, Y.sup.1Y.sup.2N--,
Y.sup.1Y.sup.2N--SO.sub.2--, [0092] alkyl optionally substituted
one or more times independently by acyloxy, hydroxy,
alkoxycarbonyl, alkoxy, carboxy, aryl, halo, alkylsulfonyl, cyano,
Y.sup.1Y.sup.2N--, or Y.sup.1Y.sup.2N--C(.dbd.O)--, [0093] acyl or
aryl, each of which is optionally substituted one or more times
independently by halo, [0094] alkoxycarbonyl optionally substituted
one or more times independently by aryl, [0095] heteroaroyl
optionally substituted one or more times independently by alkyl,
[0096] heterocyclyl optionally substituted one or more times by
oxo, or [0097] aryloxy optionally substituted one or more times
independently by haloalkyl; and [0098] Y.sup.1 and Y.sup.2 are each
independently hydrogen, alkylsulfonyl, aroyl, or alkyl optionally
substituted by morpholinyl, or [0099] Y.sup.1 and Y.sup.2 together
with the nitrogen atom to which they are attached form morpholinyl;
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof.
[0100] Another particular embodiment of the invention is a compound
of formula (I) wherein: [0101] R.sup.3 and R.sup.4 together with
the nitrogen atom to which they are attached form [1,2,4]triazolyl,
pyrrolyl, indolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl, or
pyrrolo[2,3-c]pyridyl, each of which is optionally substituted one
or more times independently by R.sup.6; [0102] R.sup.6 is alkoxy,
carboxy, cycloalkyl, halo, cyano, alkylsulfonyl,
Y.sup.1Y.sup.2N--SO.sub.2--, [0103] alkyl optionally substituted
one or more times independently by Y.sup.1Y.sup.2N--C(.dbd.O)--,
hydroxy, alkoxycarbonyl, alkoxy, carboxy, aryl, halo, heterocyclyl,
cycloalkyl, alkylsulfonyl, cyano, heterocyclylcarbonyl, [0104] acyl
or aryl, each of which is optionally substituted one or more times
independently by halo, [0105] alkoxycarbonyl optionally substituted
one or more times independently by aryl, [0106] heteroaroyl
optionally substituted one or more times independently by alkyl,
[0107] heterocyclyl optionally substituted one or more times by
oxo, or [0108] aryloxy optionally substituted one or more times
independently by haloalkyl; and [0109] Y.sup.1 and Y.sup.2 are each
independently hydrogen, or alkyl optionally substituted by
morpholinyl, or [0110] Y.sup.1 and Y.sup.2 together with the
nitrogen atom to which they are attached form morpholinyl; or a
hydrate, solvate or N-oxide thereof, or a pharmaceutically
acceptable salt thereof
[0111] Another particular embodiment of the invention is a compound
of formula (I) wherein: [0112] R.sup.3 and R.sup.4 together with
the nitrogen atom to which they are attached form imidazolidinyl,
[1,2,4]thiazinanyl, piperazinyl, morpholinyl, pyrrolidinyl,
1,2,3,4-tetrahydro-pyrimidinyl, piperidinyl, oxazolidinyl,
2,3-dihydro-indolyl, octahydro-cyclopenta[c]pyrrolyl, or
3,4-dihydro-benzo[1,4]oxazine, each of which optionally substituted
one or more times independently by R.sup.6; [0113] R.sup.6 is oxo,
alkoxy, carboxy, cycloalkyl, halo, cyano, alkylsulfonyl,
Y.sup.1Y.sup.2N--SO.sub.2--, [0114] alkyl optionally substituted
one or more times independently by hydroxy, alkoxycarbonyl, alkoxy,
carboxy, aryl, halo, heterocyclyl, cycloalkyl, alkylsulfonyl,
cyano, heterocyclylcarbonyl, [0115] acyl or aryl, each of which is
optionally substituted one or more times independently by halo,
[0116] alkoxycarbonyl optionally substituted one or more times
independently by aryl, [0117] heteroaroyl optionally substituted
one or more times independently by alkyl, [0118] heterocyclyl
optionally substituted one or more times by oxo, or [0119] aryloxy
optionally substituted one or more times independently by
haloalkyl; and [0120] Y.sup.1 and Y.sup.2 are each independently
hydrogen, or alkyl optionally substituted by morpholinyl, or [0121]
Y.sup.1 and Y.sup.2 together with the nitrogen atom to which they
are attached form morpholinyl; or a hydrate, solvate or N-oxide
thereof, or a pharmaceutically acceptable salt thereof.
[0122] Another particular embodiment of the invention is a compound
of formula (I) wherein: [0123] R.sup.3 and R.sup.4 together with
the nitrogen atom to which they are attached form indolyl,
optionally substituted one or more times independently by R.sup.6;
[0124] R.sup.6 is Y.sup.1Y.sup.2N--SO.sub.2--, alkoxycarbonyl,
carboxyalkyl, cyano, halo, alkylsulfonyl, alkoxy, or acyl
optionally substituted one or more times independently by halo; and
[0125] Y.sup.1 and Y.sup.2 are each independently hydrogen, or
alkyl optionally substituted by morpholinyl, or [0126] Y.sup.1 and
Y.sup.2 together with the nitrogen atom to which they are attached
form morpholinyl; or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
[0127] Another particular embodiment of the invention is a compound
of formula (I) wherein: [0128] R.sup.5 is phenyl, pyridyl, or
benzo[1,3]dioxolyl, each of which is optionally substituted one or
more times independently by R.sup.6; [0129] R.sup.6 is
Y.sup.1Y.sup.2N--SO.sub.2--, hydroxy, alkoxy, halo, alkyl, or
haloalkyl; and [0130] Y.sup.1 and Y.sup.2 are each independently
hydrogen or alkyl, or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
[0131] Another particular embodiment of the invention is a compound
of formula (I), which is [0132]
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide, [0133]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide, [0134]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)amide, [0135]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0136]
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0137]
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0138]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide, [0139]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0140]
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide, [0141]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0142]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide, [0143]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide, [0144]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide, [0145]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-amide, [0146]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide, [0147]
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide, [0148]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dimethyl-indol-1-yl)-amide, [0149]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-chloro-2-methyl-indol-1-yl)-amide, [0150]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-bromo-indol-1-yl)-amide, [0151]
3-Oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid benzyl ester, [0152] 2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoro-indol-1-yl)amide, [0153]
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide, [0154]
2-(3-Fluorophenyl)pyrimidine-5-carboxylicacid-[5-fluoro-3-(morpholine-4-s-
ulfonyl)indol-1-yl]amide, [0155]
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(morpholine-4-sulfonyl) indol-1-yl]amide, [0156]
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-sulfamoylindol-1-yl)amide, [0157]
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide, [0158]
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide,
[0159] 2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide, [0160]
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide,
[0161] 2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide,
[0162] 2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide, [0163]
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide, [0164]
2-(Pyridin-2-yl)-pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide, [0165]
2-(Pyridin-2-yl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide, [0166]
2-Phenyl-pyrimidine-5-carboxylic acid
[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide,
[0167] 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide, [0168]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0169]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide,
[0170] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide, [0171]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide, [0172]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyano-5-fluoro-indol-1-yl)-amide, [0173]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide, [0174]
2-Phenyl-pyrimidine-5-carboxylic acid [1,2,4]triazol-4-ylamide,
[0175] 2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-ylamide,
[0176] 2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-fluoro-phenyl)-hydrazide, [0177]
2-Phenyl-pyrimidine-5-carboxylic acid N'-ethyl-N'-tolyl-hydrazide,
[0178] 2-Phenyl-pyrimidine-5-carboxylic acid
(3-oxo-morpholin-4-yl)-amide, [0179]
2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [0180] 2-Benzoyl-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [0181] 2-Benzoyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide, [0182]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[5-trifluoromethyl-pyridin-2-yl]-hydrazide, [0183]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[4-trifluoromethyl-pyridin-2-yl]-hydrazide, [0184]
2-Phenyl-pyrimidine-5-carboxylic acid N'-pyridin-2-yl-hydrazide,
[0185] 2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-chloro-phenyl)-hydrazide, [0186]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-oxo-piperidin-1-yl)-amide, [0187]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-cyclohexyl-N'-methyl-hydrazide, [0188]
2-Phenyoxy-pyrimidine-5-carboxylic acid N'-morpholin-4-yl-amide,
[0189] 2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
[0190] 2-Phenyl-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
[0191] 2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide, [0192]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide,
[0193]
3-{2,4-Dioxo-3-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydr-
o-pyrimidin-5-yl}-propionic acid methyl ester, [0194]
3-{2,4-Dioxo-3-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydr-
o-pyrimidin-5-yl}-propionic acid, [0195]
2-Phenyl-pyrimidine-5-carboxylic acid
(4-methyl-piperazin-1-yl)-amide, [0196]
2-Phenyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide, [0197]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide, [0198]
2-Phenyl-pyrimidine-5-carboxylic acid
((s)-2-methoxymethyl)-pyrrolidin-1-yl]-amide, [0199]
2-Phenyl-pyrimidine-5-carboxylic acid
((R)-2-methoxymethyl)-pyrrolidin-1-yl]-amide, [0200]
2-Phenyl-pyrimidine-5-carboxylic acid
(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-amide, [0201]
2-Phenyl-pyrimidine-5-carboxylic acid
(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-amide, [0202]
2-Phenyl-pyrimidine-5-carboxylic acid pyrrol-1-ylamide, [0203]
2-Phenyl-pyrimidine-5-carboxylic acid
(5-morpholin-4-ylmethyl-2-oxo-oxazolidin-3-yl)-amide, [0204]
2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl]-amide, [0205]
2-Phenyl-pyrimidine-5-carboxylic acid
(2-oxo-oxazolidin-3-yl)-amide, [0206]
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl]-amide, [0207]
[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl
ester, [0208]
2-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide, [0209]
4-[3-(4-Morpholino)propyl]-1-(2-phenyl-pyrimidine-5-carbonyl)-3-th-
iosemicarbazide, [0210] 2-Phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0211]
{4-[2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-acetic
acid methyl ester, [0212] 2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyanomethyl-piperazin-1-yl)-amide, [0213] Acetic acid
2-{4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-ethyl
ester, [0214] 2-Phenyl-pyrimidine-5-carboxylic acid
(4-acetyl-piperazin-1-yl)-amide, [0215]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide, [0216]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-amide, [0217]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-methoxy-ethyl)-piperazin-1-yl]-amide, [0218]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide, [0219]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0220]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide, [0221] 2-Phenyl-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide, [0222] 2-Phenyl-pyrimidine-5-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide, [0223]
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0224]
2-Phenyl-pyrimidine-5-carboxylic acid pyrrolidin-1-yl-amide, [0225]
2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-piperadin-1-yl)-amide, [0226]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl)-amide, [0227]
2-Phenyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide, [0228]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide, [0229]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-pyridin-2-yl-hydrazide, [0230]
2-Phenyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide,
[0231] 2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0232]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid indol-1-yl-amide,
[0233] 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
indol-1-yl-amide, [0234]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0235]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide, [0236]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide, [0237]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
indol-1-ylamide, [0238]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide, [0239]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
indol-1-ylamide, [0240] 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid (5-methanesulfonyl-indol-1-yl)-amide, [0241]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methanesulfonyl-indol-1-yl)-amide, [0242]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide, [0243]
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide, [0244]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide, [0245]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0246]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide, [0247]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0248]
2-(3-Fluoro-phenyl-4-methyl)-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0249]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide, [0250]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0251]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0252]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0253]
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridine-1-ylamide, [0254]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0255]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide, [0256]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0257]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0258]
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide, [0259]
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0260]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide, [0261]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide, [0262]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-cyano-indol-1-yl)-amide, [0263]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(4-cyano-indol-1-yl)-amide, [0264]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[4-(1H-tetrazol-5-yl)-indol-1-yl]-amide, [0265]
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid methyl ester, [0266]
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid, [0267]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyanomethyl-indol-1-yl)-amide, [0268]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide, [0269]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(1H-tetrazol-5-ylmethyl)-indol-1-yl]-amide, [0270]
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazinecarboxamide, [0271]
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide,
[0272] 2-Phenyl-pyrimidine-5-carboxylic acid
(2,4-dioxo-imidazolidin-1-yl)-amide, [0273]
2-Phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0274]
2-Phenyl-pyrimidine-5-carboxylic acid N'-phenyl-hydrazide, [0275]
Pyridine-2-carboxylic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide,
[0276]
4-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-benzenesulfonami-
de, [0277] 3-Hydroxy-benzoic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide, [0278]
Benzo[1,3]dioxo-5-carboxylic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide, [0279]
3,4-Dimethoxy-benzoic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide, [0280]
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-phenyl-hydrazide, [0281]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-indol-1-yl)-amide, [0282]
2-(3-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0283]
2-(2-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0284]
2-(4-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0285]
2-(3-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0286]
2-(2-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0287]
2-(4-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide, [0288]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0289]
2-Thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0290]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0291]
[2,2']Bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide,
[0292] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-chloro-5-fluoro-indol-1-yl)-amide, [0293]
5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1-
H-indole-3-carboxylic acid amide, [0294]
2-{5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl}-2-methyl-propionic acid, [0295]
2-(5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino-
}-1H-indol-3-yl)-2-methyl-propionic acid, [0296]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide, [0297]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide, [0298]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-yl]-amide, [0299]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-formyl-indol-1-yl)-amide, [0300]
5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-ind-
ole-3-carboxylic acid, [0301]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-hydroxymethyl-indol-1-yl)-amide, [0302]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide, [0303]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide, [0304]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide, [0305]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide, [0306]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide, [0307]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide, [0308]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide, [0309]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide, [0310]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide, [0311]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide, [0312]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide, [0313]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide, [0314]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide, [0315]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide, [0316]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
[0317] 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
[0318] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
[0319] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide,
[0320] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-2-methyl-indol-1-yl)-amide, [0321]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
N',N'-diphenyl-hydrazide [0322]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(7-fluoro-3-methyl-indol-1-yl)-amide, [0323]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-3-methyl-indol-1-yl)-amide, [0324]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0325]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0326]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3c]pyridin-1-yl)-amide, [0327]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0328]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0329]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-5-trifluoromethyl-indol-1-yl)-amide, [0330]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0331]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3c]pyridin-1-yl)-amide, [0332]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0333]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0334]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0335]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-nitro-indol-1-yl)-amide, [0336]
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide, [0337]
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-(dimethanesulfonyl)-amino-indol-1-yl]-amide, [0338]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-benzoylamino-indol-1-yl)-amide, [0339]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-indol-1-yl]-amide,
[0340] 2-Pyridin-2-yl-4-trifluoromethyl-pyrimidine-5-carboxylic
acid (5-fluoro-3-methyl-indol-1-yl)-amide, [0341]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide, [0342]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide, [0343]
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide, [0344]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0345]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0346]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0347]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0348]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide, [0349]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide, [0350]
2-Pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxyl-indol-1-yl)-amide, [0351]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0352]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0353]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0354]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0355]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0356]
4-Methyl-2-(1-oxy-pyridin-2-yl)-pyrimidin-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0357]
2-(3-Difluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, or [0358]
2-(3-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0359] Another particular embodiment of the invention is a compound
of formula (I), which is: [0360] 2-Phenyl-pyrimidine-5-carboxylic
acid (4-benzyl-piperazin-1-yl)-amide, [0361]
2-Phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide, [0362]
2-Phenyl-pyrimidine-5-carboxylic acid
(4-methanesulfonyl-piperazin-1-yl)-amide, [0363]
2-(2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [0364] 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-2-carbonyl)-piperazin-1-yl]-amide, [0365]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-4-carbonyl)-piperazin-1-yl]-amide, [0366]
4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid tert-butyl ester, [0367] 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide, [0368]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide, [0369]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [0370] 2-Phenyl-pyrimidine-5-carboxylic acid
indol-1-ylamide, [0371] 2-Phenyl-pyrimidine-5-carboxylic acid
(4-methoxy-piperidin-1-yl)-amide, [0372]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide, [0373]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide, [0374]
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide, [0375]
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-3-(2-morph-
olin-4-yl-ethyl)-1H-indole-6-carboxylic acid methyl ester, [0376]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide, [0377]
N-methyl-N-(5-fluoro)-indol-3-ylsulfonyl
N'-[2-(3-fluoro)-phenyl-pyrimidine-5-carbonyl]-hydrazide, [0378]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide, [0379]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0380]
4-Methyl-2-(1-oxy)-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0381]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0382]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0383]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0384]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0385]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0386]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0387]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0388]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0389]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0390]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0391]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0392]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0393]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [0394]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0395]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0396]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0397]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0398]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0399]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0400]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0401]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0402]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0403]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0404]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0405]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0406]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0407]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl -pyrrolo[2,3-c]pyridin-1-yl)-amide, [0408]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0409]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [0410]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0411]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0412]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0413]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [0414]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0415]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0416]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0417]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0418]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0419]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [0420]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0421]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0422]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0423]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0424]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [0425]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0426]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0427]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0428]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0429]
2-(4-Methyl-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [0430]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-3-oxo-2,3-dihydro-indazol-1-yl)amide, [0431]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)amide)amide, [0432]
6-(4-Chloro-thiazol-2-yl)-2-methyl-N-pyrrolo[2,3-c]pyridin-1-yl-nicotinam-
ide, [0433] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid (5-methyl-4-oxo-4,5-dihydro-pyrrolo[3,2-c]pyridin-1-yl)amide,
[0434] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid (5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0435]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0436]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0437]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0438]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0439] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0440] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0441] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0442] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0443] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0444] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0445] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0446] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0447]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0448]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0449]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0450]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0451] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [0452]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0453] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide, [0454]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0455] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide, [0456]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0457] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide, [0458]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0459]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0460]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0461]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0462]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0463] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0464] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0465] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0466] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0467] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0468] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0469] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0470] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0471]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0472]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0473]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0474]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0475] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [0476]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0477]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [0478]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0479] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide, [0480]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0481]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0482]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0483] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide, [0484]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0485]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0486]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[0487] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide, [0488]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoro methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0489]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0490]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [0491]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
[0492] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [0493]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [0494]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [0495]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[3,2-b]pyridin-1-yl]-amide,
[0496] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[0497] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[0498] 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, [0499]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, or [0500]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
[0501] It is to be understood that this invention covers all
appropriate combinations of the particular embodiments referred
thereto.
[0502] The present invention also includes within its scope a
pharmaceutical composition comprising a pharmaceutically effective
amount of a compound of the invention, in admixture with a
pharmaceutically acceptable carrier.
[0503] Compounds of the present invention are PGDS inhibitors and
thus, are useful for treating allergic and/or inflammatory
disorders, particularly disorders such as allergic rhinitis, asthma
and/or chronic obstructive pulmonary disease (COPD). Accordingly,
another invention herein is directed to a method of treating a
patient suffering from allergic rhinitis, asthma, and/or chronic
obstructive pulmonary disease (COPD) comprising administering to
the patient a pharmaceutically effective amount of compound of
formula (I), or a hydrate, solvate or N-oxide thereof, or a
pharmaceutically acceptable salt thereof.
[0504] References herein directed to treating should be understood
to include prophylactic therapy to inhibit PGDS, as well as to
treat an established acute or chronic or physiological conditions
associated with PGDS to essentially cure a patient suffering
therefrom, or ameliorate the physiological conditions associated
therewith. Physiological conditions discussed herein include some,
but not all, of the possible clinical situations where an
anti-allergic rhinitis and/or asthma treatment is warranted. Those
experienced in this field are well aware of the circumstances
requiring treatment.
[0505] In practice, the compound of the present invention may be
administered in pharmaceutically acceptable dosage form to humans
and other mammals by topical or systemic administration, including
oral, inhalational, rectal, nasal, buccal, sublingual, vaginal,
colonic, parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), intracisternal
and intraperitoneal. It will be appreciated that the particular
route may vary with for example the physiological condition of the
recipient.
[0506] "Pharmaceutically acceptable dosage forms" refers to dosage
forms of the compound of the invention, and includes, for example,
tablets, dragees, powders, elixirs, syrups, liquid preparations,
including suspensions, sprays, inhalants tablets, lozenges,
emulsions, solutions, granules, capsules and suppositories, as well
as liquid preparations for injections, including liposome
preparations. Techniques and formulations generally may be found in
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., latest edition.
[0507] A particular aspect of the invention provides for the
compound of the invention to be administered in the form of a
pharmaceutical composition.
[0508] Pharmaceutically acceptable carriers include at least one
component selected from the group comprising pharmaceutically
acceptable carriers, diluents, coatings, adjuvants, excipients, or
vehicles, such as preserving agents, fillers, disintegrating
agents, wetting agents, emulsifying agents, emulsion stabilizing
agents, suspending agents, isotonic agents, sweetening agents,
flavoring agents, perfuming agents, coloring agents, antibacterial
agents, antifungal agents, other therapeutic agents, lubricating
agents, adsorption delaying or promoting agents, and dispensing
agents, depending on the nature of the mode of administration and
dosage forms.
[0509] Exemplary suspending agents include ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances.
[0510] Exemplary antibacterial and antifungal agents for the
prevention of the action of microorganisms include parabens,
chlorobutanol, phenol, sorbic acid, and the like.
[0511] Exemplary isotonic agents include sugars, sodium chloride,
and the like.
[0512] Exemplary adsorption delaying agents to prolong absorption
include aluminum monostearate and gelatin.
[0513] Exemplary adsorption promoting agents to enhance absorption
include dimethyl sulfoxide and related analogs.
[0514] Exemplary diluents, solvents, vehicles, solubilizing agents,
emulsifiers and emulsion stabilizers, include water, chloroform,
sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl
acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl
benzoate, polyols, propylene glycol, 1,3-butylene glycol, glycerol,
polyethylene glycols, dimethylformamide, Tween.RTM. 60, Span.RTM.
60, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate
and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable
oils (such as cottonseed oil, groundnut oil, olive oil, castor oil
and sesame oil) and injectable organic esters such as ethyl oleate,
and the like, or suitable mixtures of these substances.
[0515] Exemplary excipients include lactose, milk sugar, sodium
citrate, calcium carbonate and dicalcium phosphate.
[0516] Exemplary disintegrating agents include starch, alginic
acids and certain complex silicates. Exemplary lubricants include
magnesium stearate, sodium lauryl sulfate, talc, as well as high
molecular weight polyethylene glycols.
[0517] The choice of pharmaceutical acceptable carrier is generally
determined in accordance with the chemical properties of the active
compound such as solubility, the particular mode of administration
and the provisions to be observed in pharmaceutical practice.
[0518] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented as discrete units
such as a solid dosage form, such as capsules, cachets or tablets
each containing a predetermined amount of the active ingredient, or
as a powder or granules; as a liquid dosage form such as a solution
or a suspension in an aqueous liquid or a non-aqueous liquid, or as
an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The active ingredient may also be presented as a bolus, electuary
or paste.
[0519] "Solid dosage form" means the dosage form of the compound of
the invention is solid form, for example capsules, tablets, pills,
powders, dragees or granules. In such solid dosage forms, the
compound of the invention is admixed with at least one inert
customary excipient (or carrier) such as sodium citrate or
dicalcium phosphate or: (a) fillers or extenders, as for example,
starches, lactose, sucrose, glucose, mannitol and silicic acid, (b)
binders, as for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants,
as for example, glycerol, (d) disintegrating agents, as for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates and sodium carbonate, (e)
solution retarders, as for example paraffin, (f) absorption
accelerators, as for example, quaternary ammonium compounds, (g)
wetting agents, as for example, cetyl alcohol and glycerol
monostearate, (h) adsorbents, as for example, kaolin and bentonite,
(i) lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, (j)
opacifying agents, (k) buffering agents, and agents which release
the compound of the invention in a certain part of the intestinal
tract in a delayed manner.
[0520] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Excipients such as lactose,
sodium citrate, calcium carbonate, dicalcium phosphate and
disintegrating agents such as starch, alginic acids and certain
complex silicates combined with lubricants such as magnesium
stearate, sodium lauryl sulfate and talc may be used. A mixture of
the powdered compounds moistened with an inert liquid diluent may
be molded in a suitable machine to make molded tablets. The tablets
may optionally be coated or scored and may be formulated so as to
provide slow or controlled release of the active ingredient
therein.
[0521] Solid compositions may also be employed as fillers in soft
and hard-filled gelatin capsules using such excipients as lactose
or milk sugar as well as high molecular weight polyethylene
glycols, and the like.
[0522] If desired, and for more effective distribution, the
compound can be microencapsulated in, or attached to, a slow
release or targeted delivery systems such as a biocompatible,
biodegradable polymer matrices (e.g., poly(d,l-lactide
co-glycolide)), liposomes, and microspheres and subcutaneously or
intramuscularly injected by a technique called subcutaneous or
intramuscular depot to provide continuous slow release of the
compound(s) for a period of 2 weeks or longer. The compounds may be
sterilized, for example, by filtration through a bacteria-retaining
filter, or by incorporating sterilizing agents in the form of
sterile solid compositions that can be dissolved in sterile water,
or some other sterile injectable medium immediately before use.
[0523] "Liquid dosage form" means the dose of the active compound
to be administered to the patient is in liquid form, for example,
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compound, the liquid
dosage forms may contain inert diluents commonly used in the art,
such solvents, solubilizing agents and emulsifiers.
[0524] When aqueous suspensions are used they can contain
emulsifying agents or agents which facilitate suspension.
[0525] Pharmaceutical compositions suitable for topical
administration mean formulations that are in a form suitable to be
administered topically to a patient. The formulation may be
presented as a topical ointment, salves, powders, sprays and
inhalants, gels (water or alcohol based), creams, as is generally
known in the art, or incorporated into a matrix base for
application in a patch, which would allow a controlled release of
compound through the transdermal barrier. When formulated in an
ointment, the active ingredients may be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients may be formulated in a cream with an
oil-in-water cream base. Formulations suitable for topical
administration in the eye include eye drops wherein the active
ingredient is dissolved or suspended in a suitable carrier,
especially an aqueous solvent for the active ingredient.
Formulations suitable for topical administration in the mouth
include lozenges comprising the active ingredient in a flavored
basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0526] The oily phase of the emulsion pharmaceutical composition
may be constituted from known ingredients, in a known manner. While
the phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil. In a
particular embodiment, a hydrophilic emulsifier is included
together with a lipophilic emulsifier that acts as a stabilizer.
Together, the emulsifier(s) with, or without, stabilizer(s) make up
the emulsifying wax, and together with the oil and fat make up the
emulsifying ointment base which forms the oily dispersed phase of
the cream formulations.
[0527] If desired, the aqueous phase of the cream base may include,
for example, a least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as, propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound that enhances
absorption, or penetration of the active ingredient through the
skin, or other affected areas.
[0528] The choice of suitable oils or fats for a composition is
based on achieving the desired properties. Thus a cream should
particularly be a non-greasy, non-staining and washable product
with suitable consistency to avoid leakage from tubes or other
containers. Straight or branched chain, mono- or dibasic alkyl
esters such as di-isopropyl myristate, decyl oleate, isopropyl
palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of
branched chain esters known as Crodamol CAP may be used. These may
be used alone or in combination depending on the properties
required. Alternatively, high melting point lipids such as white
soft paraffin and/or liquid paraffin or other mineral oils can be
used.
[0529] Pharmaceutical compositions suitable for rectal or vaginal
administrations mean formulations that are in a form suitable to be
administered rectally or vaginally to a patient and containing at
least one compound of the invention. Suppositories are a particular
form for such formulations that can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax, which are solid at ordinary temperatures but
liquid at body temperature and therefore, melt in the rectum or
vaginal cavity and release the active component.
[0530] Pharmaceutical composition administered by injection may be
by transmuscular, intravenous, intraperitoneal, and/or subcutaneous
injection. The compositions of the present invention are formulated
in liquid solutions, in particular in physiologically compatible
buffers such as Hank's solution or Ringer's solution. In addition,
the compositions may be formulated in solid form and redissolved or
suspended immediately prior to use. Lyophilized forms are also
included. The formulations are sterile and include emulsions,
suspensions, aqueous and non-aqueous injection solutions, which may
contain suspending agents and thickening agents and anti-oxidants,
buffers, bacteriostats and solutes which render the formulation
isotonic, and have a suitably adjusted pH, with the blood of the
intended recipient.
[0531] Pharmaceutical composition of the present invention suitable
for nasal or inhalational administration means compositions that
are in a form suitable to be administered nasally or by inhalation
to a patient. The composition may contain a carrier, in a powder
form, having a particle size for example in the range 1 to 500
microns (including particle sizes in a range between 20 and 500
microns in increments of 5 microns such as 30 microns, 35 microns,
etc.). Suitable compositions wherein the carrier is a liquid, for
administration as for example a nasal spray or as nasal drops,
include aqueous or oily solutions of the active ingredient.
Compositions suitable for aerosol administration may be prepared
according to conventional methods and may be delivered with other
therapeutic agents. Inhalational therapy is readily administered by
metered dose inhalers or any suitable dry powder inhaler, such as
the Eclipse, Spinhaler.RTM., or Ultrahaler.RTM. as described in
patent application WO2004/026380, and U.S. Pat. No. 5,176,132.
[0532] Actual dosage levels of active ingredient(s) in the
compositions of the invention may be varied so as to obtain an
amount of active ingredient(s) that is (are) effective to obtain a
desired therapeutic response for a particular composition and
method of administration for a patient. A selected dosage level for
any particular patient therefore depends upon a variety of factors
including the desired therapeutic effect, on the route of
administration, on the desired duration of treatment, the etiology
and severity of the disease, the patient's condition, weight, sex,
diet and age, the type and potency of each active ingredient, rates
of absorption, metabolism and/or excretion and other factors.
[0533] Total daily dose of the compound of this invention
administered to a patient in single or divided doses may be in
amounts, for example, of from about 0.001 to about 100 mg/kg body
weight daily and particularly 0.01 to 10 mg/kg/day. For example, in
an adult, the doses are generally from about 0.01 to about 100,
particularly about 0.01 to about 10, mg/kg body weight per day by
inhalation, from about 0.01 to about 100, particularly 0.1 to 70,
more especially 0.5 to 10, mg/kg body weight per day by oral
administration, and from about 0.01 to about 50, particularly 0.01
to 10, mg/kg body weight per day by intravenous administration. The
percentage of active ingredient in a composition may be varied,
though it should constitute a proportion such that a suitable
dosage shall be obtained. Dosage unit compositions may contain such
amounts or such submultiples thereof as may be used to make up the
daily dose. Obviously, several unit dosage forms may be
administered at about the same time. A dosage may be administered
as frequently as necessary in order to obtain the desired
therapeutic effect. Some patients may respond rapidly to a higher
or lower dose and may find much lower maintenance doses adequate.
For other patients, it may be necessary to have long-term
treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient. It goes
without saying that, for other patients, it will be necessary to
prescribe not more than one or two doses per day.
[0534] The formulations can be prepared in unit dosage form by any
of the methods well known in the art of pharmacy. Such methods
include the step of bringing into association the pharmaceutically
active ingredient with the carrier that constitutes one or more
accessory ingredients. In general the formulations are prepared by
uniformly and intimately bringing into association the active
ingredient with liquid carriers or finely divided solid carriers or
both, and then, if necessary, shaping the product.
[0535] The formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials with elastomeric
stoppers, and may be stored in a freeze-dried (lyophilized)
condition requiring only the addition of the sterile liquid
carrier, for example water for injections, immediately prior to
use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules and tablets of the kind
previously described.
[0536] Compounds of the invention may be prepared by the
application or adaptation of known methods, by which is a meant
method used heretofore or described in the literature, for example
those described by R. C. Larock in Comprehensive Organic
Transformations, VCH publishers, 1989.
[0537] In the reactions described hereinafter it may be necessary
to protect reactive functional groups, for example hydroxy, amino,
imino, thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with
standard practice, for examples see T. W. Greene and P. G. M. Wuts,
Protecting Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons, Inc., 1999.
[0538] A compound of formula (I), wherein R.sup.2 is hydrogen,
L.sup.1 is a bond, --NH--C(.dbd.O)-- or (C.sub.1-C.sub.2)-alkylene
optionally substituted one or more times by halo, and R.sup.1,
R.sup.3 and R.sup.4 are as defined herein, may be prepared, as
shown in Scheme I below, by (i) reacting a corresponding amidine
compound of formula (I), with a reagent of formula (2) to provide a
compound of formula (3), (ii) hydrolyzing the compound of formula
(3) to provide a compound of formula (4), and (iii) coupling the
compound of (4) with a corresponding compound of formula (5).
##STR00003##
[0539] The first step reaction may conveniently be carried out, for
example, at a temperature about 100.degree. C., in an inert
solvent, such as DMF. The second step reaction may conveniently be
carried out, for example, at room temperature, in the presence of
an inorganic base, such as LiOH, KOH or NaOH, in a solvent, such as
THF, MeOH, water, or a mixture thereof. The third step reaction may
conveniently be carried out, for example, at about a temperature
about room temperature to 100.degree. C., in the presence of a
coupling agent, such as HCTU, HOTT, PyBrOP, DMTMM, or HATU with
HOAt, and a base, such as DIPEA or Et.sub.3N, in an inert solvent,
such as DMF. The third step reaction may conveniently be carried
out, for example, at about a temperature about 0.degree. C. to room
temperature, by first reacting the compound of formula (4) with
oxalyl chloride, and then adding the compound of formula (5) and a
base such as DIPEA, Et.sub.3N, K.sub.2CO.sub.3 or Na.sub.2CO.sub.3,
in an inert solvent, such as DCM or DMF.
[0540] A compound of formula (I), wherein R.sup.2 is
(C.sub.1-C.sub.4)-alkyl optionally substituted one or more times by
halo, L.sup.1 is a bond, --NH--C(.dbd.O)-- or
(C.sub.1-C.sub.2)-alkylene optionally substituted one or more times
by halo, and R.sup.1, R.sup.3 and R.sup.4 are as defined herein,
may also be prepared, as shown in Scheme II below, by (i) reacting
a corresponding amidine compound of formula (I), with a reagent of
formula (6) to provide a compound of formula (7), (ii) hydrolyzing
the compound of formula (7) to provide a compound of formula (8),
and (iii) coupling the compound of formula (8) with a corresponding
compound of formula (5).
##STR00004##
[0541] The first step reaction may conveniently be carried out, for
example, at a temperature about 100.degree. C., in the presence of
sodium metal, in a solvent, such as EtOH. The second step reaction
may conveniently be carried out, for example, at room temperature,
in the presence of an inorganic base, such as LiOH, KOH or NaOH, in
a solvent, such as THF, MeOH, water, or a mixture thereof. The
third step reaction may conveniently be carried out, for example,
at about a temperature about room temperature to 100.degree. C., in
the presence of a coupling agent, such as HCTU, HOTT, PyBrOP,
DMTMM, or HATU with HOAt, and a base, such as DIPEA or Et.sub.3N,
in an inert solvent, such as DMF. The third step reaction may
conveniently be carried out, for example, at about a temperature
about 0.degree. C. to room temperature, by first reacting the
compound of formula (8) with oxalyl chloride, and then adding the
compound of formula (5) and a base such as DIPEA, Et.sub.3N,
K.sub.2CO.sub.3 or Na.sub.2CO.sub.3, in an inert solvent, such as
DCM or DMF.
[0542] A compound of formula (I), wherein L.sup.1 is --C(.dbd.O)--,
and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined herein,
may be prepared, as shown in Scheme III below, by (1) reacting a
corresponding compound of formula (9), with a Grignard reagent of
formula R.sup.1MgBr to provide a compound of formula (10), (2)
converting the compound of formula (10) into a compound of formula
(11), and (3) hydrolyzing the compound of formula (11) to provide a
compound of formula (12), (4) hydrolyzing the compound of formula
(12) to provide a compound of formula (13) and (5) coupling the
compound of formula (13) with a corresponding compound of formula
(5).
##STR00005##
[0543] The first step reaction may conveniently be carried out, for
example, at a temperature about room temperature to 50.degree. C.,
in an inert solvent, such as Et.sub.2O. The second step reaction
may conveniently be carried out, for example, at a temperature
about 150.degree. C., in the presence of potassium
hexacyanoferrate(II) trihydrate, palladium (II) acetate and a base
such as Na.sub.2CO.sub.3 or K.sub.2CO.sub.3, in an inert solvent,
such as dimethylacetamide or DMF. The third step reaction may
conveniently be carried out, for example, at about a temperature
about 0.degree. C. to room temperature, in the presence of an
inorganic base such as KOH, NaOH or LiOH, in a solvent, such as
MeOH, or a mixture of MeOH and water. The fourth step reaction may
conveniently be carried out, for example, at room temperature, in
the presence of an inorganic base, such as LiOH, KOH or NaOH, in a
solvent, such as THF, MeOH, water, or a mixture thereof. The fifth
step reaction may conveniently be carried out, for example, at
about a temperature about room temperature to 100.degree. C., in
the presence of a coupling agent, such as HCTU, HOTT, PyBrOP,
DMTMM, or HATU with HOAt, and a base, such as DIPEA or Et.sub.3N,
in an inert solvent, such as DMF. The third step reaction may
conveniently be carried out, for example, at about a temperature
about 0.degree. C. to room temperature, by first reacting the
compound of formula (4) with oxalyl chloride, and then adding the
compound of formula (5) and a base such as DIPEA, Et.sub.3N,
K.sub.2CO.sub.3 or Na.sub.2CO.sub.3, in an inert solvent, such as
DCM or DMF.
[0544] A compound of formula (I), wherein L.sup.1 is --O--, and
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined herein, may be
prepared, as shown in Scheme IV below, by (i) oxidizing a compound
of formula (14) to provide a compound of formula (15), (ii)
reacting the compound of formula (15) with a corresponding compound
having formula R.sup.10Na to provide a compound of formula (16),
(iii) hydrolyzing the compound of formula (16) to provide a
compound of formula (17), and (iv) coupling the compound of formula
(17) with a corresponding compound of formula (5).
##STR00006##
[0545] The first step oxidation reaction may conveniently be
carried out, for example, at room temperature, in the presence of
MCPBA and Na.sub.2S.sub.2O.sub.3, in an inert solvent, such as DCM.
The second step reaction may conveniently be carried out, for
example, in a microwave heated at a temperature about 100.degree.
C., in an inert solvent, such as NMP. The third step reaction may
conveniently be carried out, for example, at about a temperature
about 0.degree. C. to room temperature, in the presence of an
inorganic base such as KOH, NaOH or LiOH, in a solvent, such as
THF, MeOH, or a mixture thereof. The fourth step reaction may
conveniently be carried out, for example, at about a temperature
about room temperature to 100.degree. C., in the presence of a
coupling agent, such as HCTU, HOTT, PyBrOP, DMTMM, or HATU with
HOAt, and a base, such as DIPEA or Et.sub.3N, in an inert solvent,
such as DMF. The third step reaction may conveniently be carried
out, for example, at about a temperature about 0.degree. C. to room
temperature, by first reacting the compound of formula (17) with
oxalyl chloride, and then adding the compound of formula (5) and a
base such as DIPEA, Et.sub.3N, K.sub.2CO.sub.3 or Na.sub.2CO.sub.3,
in an inert solvent, such as DCM or DMF.
[0546] Compounds of the invention may also be prepared by
interconversion of other compounds of the invention.
[0547] It will be appreciated that compounds of the present
invention may contain asymmetric centers. These asymmetric centers
may independently be in either the R or S configuration. It will be
apparent to those skilled in the art that certain compounds of the
invention may also exhibit geometrical isomerism. It is to be
understood that the present invention includes individual
geometrical isomers and stereoisomers and mixtures thereof,
including racemic mixtures, of compounds of Formula (I)
hereinabove. Such isomers can be separated from their mixtures, by
the application or adaptation of known methods, for example
chromatographic techniques and recrystallization techniques, or
they are separately prepared from the appropriate isomers of their
intermediates.
[0548] The compounds of the invention, their methods or preparation
and their biological activity will appear more clearly from the
examination of the following examples that are presented as an
illustration only and are not to be considered as limiting the
invention in its scope. Compounds of the invention are identified,
for example, by the following analytical methods.
[0549] Mass Spectra (MS) are recorded using a Micromass LCT mass
spectrometer. The method is positive electrospray ionization,
scanning mass m/z from 100 to 1000.
[0550] 300 MHz .sup.1H nuclear magnetic resonance spectra (.sup.1H
NMR) are recorded at ambient temperature using a Varian Mercury
(300 MHz) spectrometer with an ASW 5 mm probe. In the .sup.1H NMR
chemical shifts (.delta.) are indicated in parts per million (ppm)
with reference to tetramethylsilane (TMS) as the internal
standard.
[0551] As used in the examples and preparations that follow, as
well as the rest of the application, the terms used therein shall
have the meanings indicated: "kg"=kilograms, "g"=grams,
"mg"=milligrams, ".mu.g"=micrograms, "mol"=moles,
"mmol"=millimoles, "M"=molar, "mM"=millimolar, ".mu.M"=micromolar,
"nM"=nanomolar, "L"=liters, "mL" or "ml"=milliliters,
".mu.L"=microliters, "OC"=degrees Celsius, "mp" or "m.p."=melting
point, "bp" or "b.p."=boiling point, "mm of Hg"=pressure in
millimeters of mercury, "cm"=centimeters, "nm"=nanometers,
"abs."=absolute, "conc."=concentrated, "c"=concentration in g/mL,
"rt"=room temperature, "TLC"=thin layer chromatography, "HPLC"=high
performance liquid chromatography, "i.p."=intraperitoneally,
"i.v."=intravenously, "s"=singlet, "d"=doublet; "t"=triplet;
"q"=quartet; "m"=multiplet, "dd"=doublet of doublets; "br"=broad,
"LC"=liquid chromatograph, "MS"=mass spectrograph,
"ESI/MS"=electrospray ionization/mass spectrograph, "RT"=retention
time, "M"=molecular ion, "PSI"=pounds per square inch,
"DMSO"=dimethyl sulfoxide, "DMF".dbd.N,N-dimethylformamide,
"DCM"=dichloromethane, "HCl"=hydrochloric acid, "SPA"=Scintillation
Proximity Assay, "EtOAc"=ethyl acetate, "PBS"=Phosphate Buffered
Saline, "IUPAC"=International Union of Pure and Applied Chemistry,
"MHz"=megahertz, "MeOH"=methanol, "N"=normality,
"THF"=tetrahydrofuran, "min"=minute(s), "N.sub.2"=nitrogen gas,
"MeCN" or "CH.sub.3CN"=acetonitrile, "Et.sub.2O"=ethyl ether,
"TFA"=trifluoroacetic acid, ","=approximately,
"MgSO.sub.4"=magnesium sulfate, "Na.sub.2SO.sub.4"=sodium sulfate,
"NaHCO.sub.3"=sodium bicarbonate, "Na.sub.2CO.sub.3"=sodium
carbonate, "MCPBA"=3-Chloroperoxybenzoic acid,
"NMP"=N-methylpyrrolidone, "PS-DCC"=polymer
supported-dicyclohexylcarbodiimde, "LiOH"=Lithium hydroxide,
"PS-trisamine"=polymer supported-trisamine, "PGH2"=prostaglandin
H2, "PGD2"=prostaglandin D2; "PGE2"=prostaglandin E2,
"hPGDS"=Hematopoietic PGD2 Synthase, "GSH"=glutathione (reduced),
"EIA"=Enzyme immunoassay, "KH2PO.sub.4"=potassium phosphate,
monobasic, "K.sub.2HPO.sub.4"=potassium phosphate, dibasic,
"FeCl.sub.2"=ferrous chloride, "MOX"=methoxyl amine;
"EtOH"=ethanol, "DMSO"=dimethylsulfoxide, "Ag.sub.2O"=silver(I)
oxide,
"HATU"=O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate, "HOAt"=1-hydroxy-7-azabenzotriazole,
"DIPEA"=N,N-diisopropylethylamine,
"HOTT"=S-(1-Oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium
hexafluorophosphate,
"HCTU"=N,N',N',N'-tetramethyl-O-(6-chloro-1H-benzotriazol-1-yl)uronium
hexafluorophosphate., "PyBrOP"=bromo-tris-pyrrolidinophosphonium
hexafluorophosphate, "LiAlH.sub.4"=lithium aluminum hydride,
"PyAOP"=(7-azabenzotriazol-1-yloxy)-tripyrrolidinophosphonium
hexafluorophosphate,
"TBTU"=O-benzotriazol-1-yl-N,N,N,N,-tetramethyluronium
tetrafluoroborate, "NaHMDS"=sodium bis(trimethylsilyl)amide,
"NMP"=N-methyl-2-pyrrolidinone, "HOSA"=hydroxylamine-O-sulfonic
acid,
"DMTMM"=4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride, "TMSN.sub.3"=trimethylsily azide,
"TBAF"=tetrabutylammonium fluoride, "TFAA"=trifluoro acetic
anhydride.
EXAMPLES
Example 1
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide
##STR00007##
[0553] Step 1: A solution of potassium tert-butoxide (1.84 g, 16.43
mmol) and 5-fluoro-2-methylindole (1.21 g, 8.09 mmol) in DMF (20
mL) is stirred under N.sub.2 at rt for 60 min. A solution of
monochloroamine in ether (65 mL, 9.75 mmol) is added via an
addition funnel over 10 min. The resulting mixture is stirred at
23.degree. C. for 2 hours, and then concentrated in vacuo. The
residue is partitioned between EtOAc and water. The organic phase
is separated, washed with saturated aqueous NaHCO.sub.3, water and
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 10%
EtOAc in heptane to afford 5-fluoro-2-methyl-indol-1-ylamine (290
mg, 22%) as a solid. MS: 165 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.24-7.19 (m, 1H), 7.12 (dd, 1H), 6.92 (dt,
1H), 6.12 (s, 1H), 4.23 (br s, 2H), 2.39 (s, 3H).
[0554] Step 2: A 250 mL, three-neck, round-bottom flask equipped
with a magnetic stirrer and a reflux condenser is purged with
N.sub.2. The flask is charged sequentially with methyl
3,3-dimethoxypropionate (5.22 g, 35.3 mmol), anhydrous
1,2-dimethoxyethane (25 mL), anhydrous methyl formate (5 mL), 60%
sodium hydride (1.7 g, 42.5 mmol), and the mixture warmed to
40-50.degree. C. until evolution of hydrogen gas stops. The
reaction mixture is cooled in an ice/water bath and slowly allowed
to reach room temperature overnight with stirring. Anhydrous ether
(25 mL) is added, and the resulting suspension is filtered under
N.sub.2, washed with anhydrous ether (10 mL), and vacuum dried for
2 hours to yield sodium salt of
2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (3.51 g, 50%)
as a powder. .sup.1H NMR (CD.sub.3OD): .delta. 3.33 (s, 6H), 3.60
(s, 3H), 5.31 (s, 1H), 8.89 (s, 1H). (see: P. Zhichkin, D. J.
Fairfax, S. A. Eisenbeis, Synthesis, 2002, 720-722.)
[0555] Step 3: To a solution of nicotinamidine hydrochloride (1 g,
6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of
2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36
mmol) and the reaction mixture is heated at 100.degree. C. under
N.sub.2 for 3 hours. After this time the reaction is cooled to room
temperature and water (48 mL) is added. The precipitate is
collected by filtration, washed with water and vacuum dried to
afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester
(0.7 g, 51%). MS: 216 (M+H).
[0556] Step 4: A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic
acid methyl ester (0.73 g, 3.32 mmol) and 1M aqueous LiOH (3.32 mL)
in MeOH (5 mL) is stirred at rt overnight. The MeOH is removed in
vacuo, and the aqueous solution is treated with 3 N aqueous HCl to
adjust the pH 2-3. The solid is filtered off and washed with water
and dried in vacuum to yield 2-pyridin-3-yl-pyrimidine-5-carboxylic
acid (0.2 g, 30%) as a solid. MS: 202 (M+H).
[0557] Step 5: A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic
acid (506 mg, 2.13 mmol), HCTU (970 mg, 2.34 mmol), and DIPEA (1
mL, 5.72 mmol) in DMF (10 mL) is stirred at rt under N.sub.2 for 10
min. 5-Fluoro-2-methyl-indol-1-ylamine (311 mg, 1.89 mmol) is
added. The resulting mixture is stirred at 75.degree. C. overnight.
The mixture is cooled and portioned between EtOAc and water. The
organic phase is separated, washed with saturated aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 45% EtOAc in heptane to afford
2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide (300 mg, 46%) as a solid. MS:
348 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.02 (s,
1H), 9.60 (d, 1H), 9.49 (s, 2H), 8.82-8.76 (m, 2H), 7.64 (dd, 1H),
7.39 (dd, 1H), 7.29 (dd, 1H), 6.94 (dt, 1H), 6.35 (s, 1H), 2.33 (s,
3H).
Example 2
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide
##STR00008##
[0559] Step 1: Na.sup.0 (0.66 g, 28.6 mmol) is added to anhydrous
EtOH (100 mL) and stirred at rt for 15 min. 3-Fluorobenzamidine
hydrochloride (4.87 g, 27.8 mmol) is added and the solution is
stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid
ethyl ester (5.3 g, 28.6 mmol,) is added and the reaction mixture
is heated at reflux under N.sub.2 for 1 hours. The reaction is
cooled to rt and concentrated in vacuo. The residue is dissolved in
EtOAc (300 mL), washed with brine (2.times.100 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl
ester (6.8 g, 99%). MS: 261 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.43 (t, J=7.0 Hz, 3H), 2.92 (s, 3H), 4.42 (q,
J=7.0 Hz, 2H), 7.24 (m, 1H), 7.45 (m, 1H), 8.27 (m, 1H), 8.37 (m,
1H), 9.21 (s, 1H).
[0560] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl
ester (6.7 g, 27.2 mmol) and NaOH (2.1 g, 54.4 mmol) in a 1:1:1
solution of THF, MeOH and water (300 mL) is heated at reflux for 45
min. The THF/MeOH is evaporated, and the aqueous solution is
treated with 3 N HCl to adjust the pH to between 2 and 3. The solid
is filtered off, washed with water and dried in vacuo to yield
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5.4 g,
91%) as a solid. MS: 233 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 2.85 (s, 3H), 7.24 (m, 1H), 7.50 (m, 1H), 8.17 (m, 1H),
8.32 (m, 1H), 9.20 (s, 1H).
[0561] Step 3: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (340 mg,
1.46 mmol, prepared according to the general procedure described in
Example 1, steps 3 and 4), HOAt (248 mg, 1.82 mmol), and HATU (645
mg, 1.70 mmol) in DMF (15 mL) is stirred at rt under N.sub.2 for 20
min. 5-Fluoro-2-methyl-indol-1-ylamine (237 mg, 1.44 mmol) and
DIPEA (380 .mu.L, 2.18 mmol) are added. The resulting mixture is
stirred at 80.degree. C. overnight. The mixture is cooled and
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 20% EtOAc in
heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide (300 mg, 55%) as a solid. MS:
379 (M+H). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.14 (s, 1H),
8.38-8.20 (m, 3H), 7.56-7.52 (m, 1H), 7.30-7.27 (m, 2H), 7.19-7.16
(m, 1H), 6.96-6.90 (m, 1H), 6.32 (s, 1H), 2.83 (s, 3H), 2.42 (s,
3H).
Example 3
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)amide
##STR00009##
[0563] Step 1: A suspension of NaH (2.01 g, 50.3 mmol, 60% in
mineral oil) in DMF (45 mL) at 0.degree. C. is treated with
5-fluoro-3-methyl-1H-indole (500 mg, 3.55 mmol), and the mixture is
stirred at 0.degree. C. for 1 h. NH.sub.2OSO.sub.3H (1.9 g, 16.75
mmol) is added portion wise, and the mixture is then warmed to rt
and stirred for 2 h. The mixture is quenched with MeOH, diluted
with water, extracted with EtOAc, dried (Na.sub.2SO.sub.4),
filtered and concentrated to afford
5-fluoro-3-methyl-indol-1-ylamine. MS: 165 (M+H); .sup.1H NMR (300
MHz, CD.sub.3OD): .delta. 2.22 (s, 3H), 6.86 (m, 1H), 6.99 (s, 1H),
7.08 (m, 1H), 7.36 (m, 1H).
[0564] Step 2: Na.sup.0 (31.7 mmol) is added to anhydrous EtOH (100
mL) and stirred at rt for 15 min. Pyridine-2-carboxamidine
hydrochloride (31.7 mmol) is added and the solution is stirred for
15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester
(31.7 mmol) is added and the reaction mixture is heated at reflux
under N.sub.2 for 1 h. The reaction is cooled to rt and
concentrated in vacuo. The residue is dissolved in EtOAc (200 mL),
washed with brine (2.times.100 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid ethyl ester
(6.77 g, 88%). MS: 261 (M+H); .sup.1H .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.44 (t, 3H), 2.97 (s, 3H), 4.44 (q, 2H), 7.44
(m, 1H), 7.91 (m, 1H), 8.60 (m, 1H), 8.90 (m, 1H), 9.31 (s,
1H).
[0565] Step 3: A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid ethyl ester
(26.7 mmol) and LiOH (53.4 mmol) in a 1:1:1 solution of THF, MeOH
and water (200 mL) is stir at rt overnight. The THF/MeOH is
evaporated, and the aqueous solution is treated with 10% aqueous
HCl to adjust the pH to between 1.5 and 2.5. The solid is filtered
off, washed with water and dried in vacuo to yield
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5.50 g, 96%)
as a solid. MS: 233 (M+H); .sup.1H .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta.=2.93 (s, 3H), 7.59 (m, 1H), 8.05 (t, 1H), 8.62
(d, 1H), 8.76 (d, 1H), 9.28 (s, 1H).
[0566] Step 4, Method A:
[0567] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (335 mg, 1.56
mmol), HOTT (638 mg, 1.72 mmol), and DIPEA) (700 .mu.L, 4.01 mmol
in DMF (6 mL) is stirred stirred at rt under N.sub.2 for 20 min.
5-Fluoro-3-methyl-indol-1-ylamine (241 mg, 1.47 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 60% EtOAc in
heptane to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic
acid (5-fluoro-3-methyl-indol-1-yl)amide (193 mg, 36%) as a solid.
MS: 362 (M+H). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 10.41 (s,
1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.48-8.45 (m, 1H), 7.86 (t, 1H),
7.40-7.36 (m, 1H), 7.24-7.20 (m, 2H), 7.05-7.01 (m, 2H), 2.82 (s,
3H), 2.32 (s, 3H).
[0568] Step 4, Method B:
[0569] 5-Fluoro-3-methyl-indol-1-ylamine (10.6 mmol) is treated
with 4-methyl-2-pyridin-2-ylpyrimidine-5-carboxylic acid (2.75 g,
12.8 mmol) in DMF (75 mL) and the mixture is stirred at rt for 10
min. The mixture is then treated with
2,4-dimethoxy-6-(4-methylmorpholin-4-yl)-[1,3,5]triazine chloride
(3.82 g, 13.85 mmol) and stirred at 60.degree. C. for 1 h. The
mixture is concentrated in vacuo. The residue is diluted with
Et.sub.2O (50 mL) and 10% NaHCO.sub.3 (50 mL), and the mixture is
stirred at rt for 20 min. The resulting solid is filtered, washed,
and dried to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic
acid (5-fluoro-3-methyl-indol-1-yl)amide (3.2 g, 83%). The solid is
crystallized with MeOH:water (4:1) to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)amide as a crystal. MS: 362 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.27 (s, 3H), 2.78 (s,
3H), 7.06 (m, 1H), 7.34 (m, 1H), 7.37 (s, 1H), 7.44 (m, 1H), 7.59
(m, 1H), 8.05 (m, 1H), 8.45 (m, 1H), 8.80 (m, 1H), 9.25 (s, 1H).
IC.sub.50=7 nM.
Example 4
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00010##
[0571] Step 1: Following the procedures similar to those of Example
1, step 3, but substituting pyridine-2-carboxamidine hydrochloride
nicotinamidine hydrochloride, there is prepared
2-pyridin-2-yl-pyrimidine-5-carboxylic acid methyl ester.
[0572] Step 2: Following the procedures similar to those of Example
2, step 1, but substituting 2-pyridin-2-yl-pyrimidine-5-carboxylic
acid methyl ester for 2-pyridin-3-yl-pyrimidine-5-carboxylic acid
methyl ester, there is prepared
2-pyridin-2-yl-pyrimidine-5-carboxylic acid.
[0573] Step 3: A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic
acid (209 mg, 0.88 mmol), HOTT (435 mg, 1.17 mmol), and DIPEA (400
.mu.L, 2.29 mmol) in DMF (10 mL) is stirred at rt under N.sub.2 for
20 min. 5-Fluoro-3-methyl-indol-1-ylamine (125 mg, 0.76 mmol) is
added. The resulting mixture is stirred at rt overnight. The
mixture is portioned between EtOAc and water. The organic phase is
separated, washed with saturated aqueous NaHCO.sub.3, water and
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 70%
EtOAc in heptane to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic
acid (5-fluoro-3-methyl-indol-1-yl)-amide (180 mg, 68%) as a solid.
MS: 348 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.12
(s, 1H), 9.47 (s, 2H), 8.82 (d, 1H), 8.51 (d, 1H), 8.05 (td, 1H),
7.62 (dd, 1H), 7.42 (dd, 1H), 7.35 (dd, 1H), 7.33 (s, 1H), 7.03
(td, 1H), 2.27 (s, 3H).
Example 5
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00011##
[0575] Step 1: Following the procedures similar to those of Example
2, step 1, but substituting nicotinamidine hydrochloride for
3-fluorobenzamidine hydrochloride, there is prepared
2-pyridin-3-yl-4-methyl-pyrimidine-5-carboxylic acid ethyl
ester.
[0576] Step 2: Following the procedures similar to those of Example
2, step 1, but substituting
2-pyridin-3-yl-4-methyl-pyrimidine-5-carboxylic acid ethyl ester
for 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl
ester, there is prepared
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid.
[0577] Step 3: A solution of
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (502 mg, 2.33
mmol), HCTU (1.054 g, 2.55 mmol), and DIPEA (1.10 mL, 6.30 mmol) in
DMF (10 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3-methyl-indol-1-ylamine (341 mg, 2.08 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
triturated in ether (4 times) to afford
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (160 mg, 21%) as a solid. MS:
362 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.86 (s,
1H), 9.58 (s, 1H), 9.24 (s, 1H), 8.79-8.78 (m, 1H), 8.74 (td, 1H),
7.62 (dd, 1H), 7.44 (dd, 1H), 7.37-7.36 (m, 2H), 7.06 (td, 1H),
2.78 (s, 3H), 2.27 (s, 3H).
Example 6
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00012##
[0579] A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(664 mg, 2.79 mmol), HCTU (1.27 g, 3.07 mmol), and DIPEA (1.4 mL,
8.02 mmol) in DMF (15 mL) is stirred at rt under N.sub.2 for 10
min. 5-fluoro-3-methyl-indol-1-ylamine (491 mg, 2.55 mmol) is
added. The resulting mixture is stirred at rt overnight. The
mixture is portioned between EtOAc and water. The organic phase is
separated, washed with saturated aqueous NaHCO.sub.3, water and
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
residue is triturated in ether (3 times) and methanol to afford
2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (375 mg, 42%) as a solid. MS:
348 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.10 (s,
1H), 9.61-9.60 (m, 1H), 9.45 (s, 2H), 8.81-8.80 (m, 1H), 8.77 (dt,
1H), 7.64 (dd, 1H), 7.41 (dd, 1H), 7.35 (dd, 1H), 7.32 (s, 1H),
7.03 (td, 1H), 2.27 (s, 3H). IC.sub.50=10 nM.
Example 7
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide
##STR00013##
[0581] A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(485 mg, 2.04 mmol), HCTU (909 mg, 2.2 mmol), and DIPEA (1 mL, 5.72
mmol) in DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-2-methyl-indol-1-ylamine (299 mg, 1.82 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 70% EtOAc in
heptane to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide (112 mg, 18%) as a solid. MS:
348 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.03 (s,
1H), 9.51 (s, 2H), 8.83 (d, 1H), 8.50 (d, 1H), 8.05 (dt, 1H), 7.62
(dd, 1H), 7.39 (dd, 1H), 7.28 (dd, 1H), 6.94 (dt, 1H), 6.35 (s,
1H), 2.33 (s, 3H).
Example 8
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00014##
[0583] Step 1: To a solution of 3-fluoro-benzamidine hydrochloride
(4 g, 22.6 mmol) in anhydrous DMF (35 mL) is added sodium
3,3-dimethoxy-2-carbomethoxyprop-1-en-1-oxide (4.99 g, 25.2 mmol).
The reaction mixture is heated at 100.degree. C. under N.sub.2 for
3 h and then cooled to rt. Water (150 mL) is added and the mixture
is extracted with EtOAc. The organic layer is washed with brine,
dried (MgSO.sub.4) filtered and concentrated in vacuo to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid methyl ester (1.76
g, 34%). MS: 233 (M+H).
[0584] Step 2: To a solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid methyl ester (1.76
g, 7.58 mmol) in anhydrous MeOH (35 mL) is added LiOH (0.38 g, 15.9
mmol) and the reaction mixture is stirred at rt overnight. The
mixture is concentrated in vacuo and the residue is partitioned
between EtOAc and 3 N aqueous HCl (7.6 mL). The mixture is
extracted with EtOAc and the organic layer is washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1.62 g, 98%) as a
solid. MS: 219 (M+H).
[0585] Step 3: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (372 mg, 1.7
mmol), HCTU (757 mg, 1.83 mmol), and DIPEA (780 .mu.L, 4.47 mmol)
in DMF (10 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3-methyl-indol-1-ylamine (250 mg, 1.52 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
triturated in ether to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (332 mg, 60%) as a solid. MS:
365 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.08 (s,
1H), 9.43 (s, 2H), 8.36 (d, 1H), 8.20 (dt, 1H), 7.70-7.62 (m, 1H),
7.48 (dt, 1H), 7.40 (dd, 1H), 7.35 (dd, 1H), 7.32 (s, 1H), 7.03
(dt, 1H), 2.27 (s, 3H).
Example 9
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide
##STR00015##
[0587] A solution of
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (504 mg, 2.34
mmol), HCTU (1.06 g, 2.55 mmol), and DIPEA (1.11 mL, 6.30 mmol) in
DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-2-methyl-indol-1-ylamine (346 mg, 2.11 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 70% EtOAc in
heptane to afford 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic
acid (5-fluoro-2-methyl-indol-1-yl)-amide (82 mg, 11%) as a solid.
MS: 362 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.80
(s, 1H), 9.59 (d, 1H), 9.29 (s, 1H), 8.80-8.73 (m, 2H), 7.63 (dd,
1H), 7.22 (dd, 1H), 7.28 (dd, 1H), 6.97 (dt, 1H), 6.35 (s, 1H),
2.79 (s, 3H), 2.37 (s, 3H).
Example 10
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00016##
[0589] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (645 mg,
2.78 mmol), HCTU (1.25 g, 3.02 mmol), and DIPEA (1.35 mL, 7.73
mmol) in DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3-methyl-indol-1-ylamine (380 mg, 2.31 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
triturated in ether to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (533 mg, 61%) as a solid. MS:
379 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.84 (s,
1H), 9.21 (s, 1H), 8.32 (d, 1H), 8.17-8.15 (m, 1H), 7.66-7.61 (m,
1H), 7.47-41 (m, 2H), 7.36-7.34 (m, 2H), 7.05 (dt, 1H), 2.76 (s,
3H), 2.26 (s, 3H). IC.sub.50=6 nM.
Example 11
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide
##STR00017##
[0591] A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid (389 mg, 1.78 mmol), HOAt (290 mg, 2.13 mmol), and HATU (811
mg, 2.13 mmol) in DMF (20 mL) is stirred at rt under N.sub.2 for 20
min. 5-Fluoro-2-methyl-indol-1-ylamine (290 mg, 1.77 mmol) and
DIPEA (450 .mu.L, 2.58 mmol) are added. The resulting mixture is
stirred at 80.degree. C. overnight. The mixture is cooled and
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 25% DCM in
heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)amide (300 mg, 47%) as a solid. MS:
365 (M+H). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.23 (s, 1H),
8.76 (s, 1H), 8.35-8.22 (m, 2H), 7.54-7.45 (m, 1H), 7.19-6.86 (m,
5H), 6.25 (s, 1H), 2.29 (s, 3H).
Example 12
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide
##STR00018##
[0593] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (810 mg, 3.76
mmol), PyBrOP (1.76 g, 3.78 mmol), and DIPEA (1.9 mL, 10.89 mmol)
in DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-2-methyl-indol-1-ylamine (560 mg, 3.41 mmol) is added. The
resulting mixture is stirred at rt overnight. The mixture is
portioned between EtOAc and water. The organic phase is separated,
washed with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 3% MeOH in DCM
to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-2-methyl-indol-1-yl)-amide (174 mg, 14%) as a solid. MS:
362 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.82 (s,
1H), 9.30 (d, 1H), 8.81 (d, 1H), 8.46 (d, 1H), 8.03 (dt, 1H), 7.59
(dd, 1H), 7.43 (dd, 1H), 7.29 (dd, 1H), 6.98 (dt, 1H), 6.35 (s,
1H), 2.79 (s, 3H), 2.38 (s, 3H). IC.sub.50=8 nM.
Example 13
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide
##STR00019##
[0595] Step 1: Isoamyl nitrite (3.4 mL, 25.42 mmol) is added to a
solution of 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (3.75 g,
22.69 mmol) in DCM. The mixture is refluxed overnight. The mixture
is cooled and portioned between DCM and water. The organic phase is
separated, washed with saturated aqueous NaHCO.sub.3, water and
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo to
afford 5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.23
g, 96%) as a solid. MS: 195 (M+H). .sup.1H NMR (300 MHz,
CD.sub.3Cl)): .delta. 7.77 (dd, 1H), 7.08-6.98 (m, 2H), 3.94 (s,
2H), 1.39 (s, 6H).
[0596] Step 2: To a solution of
5-fluoro-3,3-dimethyl-1-nitroso-2,3-dihydro-1H-indole (4.03 g,
20.75 mmol) in THF (70 mL) at 0.degree. C. is added a solution of
LiAlH.sub.4 (40 mL, 40 mmol) in THF dropwise. The mixture is
allowed to warm to rt and stirred overnight. The mixture is
quenched with a saturated aqueous solution of Rochelle's Salt. The
resulting mixture is stirred until a slurry is obtained. The
organic phase is separated, washed with 10% aqueous HCl, saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 25% EtOAc in heptane to afford
5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (3.51 g, 94%) as
an oil. MS: 181 (M+H). .sup.1H NMR (300 MHz, CD.sub.3Cl)): .delta.
6.85-6.78 (m, 1H), 6.75-6.68 (m, 2H), 3.44 (br s, 2H), 3.14 (s,
2H), 1.28 (s, 6H).
[0597] Step 3: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (348 mg,
1.5 mmol), HOTT (618 mg, 1.66 mmol), and DIPEA (700 .mu.L, 4.01
mmol) in DMF (10 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (239 mg, 1.33
mmol) is added. The resulting mixture is stirred at 80.degree. C.
overnight. The mixture is cooled and portioned between EtOAc and
water. The organic phase is separated, washed with saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 15% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (416 mg, 80%)
as a solid. MS: 395 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 10.43 (s, 1H), 8.99 (s, 1H), 8.28 (d, 1H), 8.15-8.11 (m,
1H), 7.66-7.58 (m, 1H), 7.46-7.39 (m, 1H), 7.06 (dd, 1H), 6.95-6.88
(m, 1H), 6.75-6.71 (m, 1H), 3.51 (s, 2H), 2.68 (s, 3H), 1.33 (s,
6H).
Example 14
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-amide
##STR00020##
[0599] Step 1: Following procedures similar to those of Example 1,
step 1, but substituting 3-(2,2,2-trifluoro-acetyl)indole for
5-fluoro-2-methylindole,
1-(1-amino-1H-indol-3-yl)-2,2,2-trifluoro-ethanone is prepared.
[0600] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (360 mg,
1.55 mmol), HOTT (628 mg, 1.69 mmol), and DIPEA (740 .mu.L, 4.24
mmol) in DMF (10 mL) is stirred at rt under N.sub.2 for 10 min.
1-(1-Amino-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (322 mg, 1.4
mmol) is added. The resulting mixture is stirred at 80.degree. C.
overnight. The mixture is cooled and portioned between EtOAc and
water. The organic phase is separated, washed with saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue is purified by HPLC reverse
phase column chromatography eluting with a mobile phase of 0.1%
TFA/water through 100% MeCN in a 30 min. ramp to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-amide (71 mg, 11%) as a
solid. MS: 443 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
12.56 (s, 1H), 9.32 (s, 1H), 8.90 (d, 1H), 8.35 (d, 1H), 8.30-8.27
(m, 1H), 8.22-8.17 (m, 1H), 7.75-72 (m, 1H), 7.69-7.62 (m, 1H),
7.52-7.44 (m, 3H), 2.81 (s, 3H).
Example 15
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide
##STR00021##
[0602] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (685 mg, 3.18
mmol), HOTT (1.29 g, 3.48 mmol), and DIPEA (1.6 mL, 9.16 mmol) in
DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (542 mg, 3.01
mmol) is added. The resulting mixture is stirred at 80.degree. C.
overnight. The mixture is cooled and portioned between EtOAc and
water. The organic phase is separated, washed with saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 2% MeOH in DCM to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (585 mg, 52%)
as a solid. MS: 378 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 10.46 (s, 1H), 9.02 (s, 1H), 8.78 (d, 1H), 8.42 (d, 1H),
8.00 (dt, 1H), 7.56 (dd, 1H), 7.06 (dd, 1H), 6.92 (dt, 1H),
6.76-6.72 (m, 1H), 3.32 (s, 2H), 2.70 (s, 3H), 1.33 (s, 6H).
Example 16
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide
##STR00022##
[0604] A solution of
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid (706 mg, 3.28
mmol), HOTT (1.34 g, 3.6 mmol), and DIPEA (1.65 mL, 9.45 mmol) in
DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (560 mg, 3.11
mmol) is added. The resulting mixture is stirred at 80.degree. C.
overnight. The mixture is cooled and portioned between EtOAc and
water. The organic phase is separated, washed with saturated
aqueous NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 35% EtOAc in heptane to afford
4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (617 mg, 53%)
as a solid. MS: 378 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 10.44 (s, 1H), 9.55-9.54 (m, 1H), 9.01 (s, 1H), 8.77-8.75
(m, 1H), 8.72-8.68 (m, 1H), 7.60 (dd, 1H), 7.06 (dd, 1H), 6.96-6.88
(m, 1H), 6.76-6.72 (m, 1H), 3.51 (s, 2H), 2.70 (s, 3H), 1.33 (s,
6H).
Example 17
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dimethyl-indol-1-yl)-amide
##STR00023##
[0606] Step 1: Following procedures similar to those of Example 1,
step 1, but substituting 2,3-dimethylindole for
5-fluoro-2-methylindole, there is prepared
2,3-dimethyl-indol-1-ylamine as a solid. MS: 161 (M+H). .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 7.48-7.45 (m, 1H), 7.33-7.30 (m,
1H), 7.19-7.13 (m, 1H), 7.10-7.05 (m, 1H), 4.40 (br s, 2H), 2.37
(s, 3H), 2.23 (s, 3H).
[0607] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (764 mg,
3.29 mmol), HOTT (1.33 g, 3.58 mmol), and DIPEA (1.65 mL, 9.45
mmol) in DMF (15 mL) is stirred at rt under N.sub.2 for 10 min.
2,3-Dimethyl-indol-1-ylamine (497 mg, 3.1 mmol) is added. The
resulting mixture is stirred at 80.degree. C. overnight. The
mixture is cooled and portioned between EtOAc and water. The
organic phase is separated, washed with saturated aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 20% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dimethyl-indol-1-yl)-amide (568 mg, 49%) as a solid. MS: 375
(M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.68 (s, 1H),
9.24 (s, 1H), 8.33 (d, 1H), 8.20-8.15 (m, 1H), 7.69-7.61 (m, 1H),
7.50-7.43 (m, 2H), 7.37 (d, 1H), 7.17-7.05 (m, 2H), 2.78 (s, 3H),
2.30 (s, 3H), 2.24 (s, 3H).
Example 18
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-chloro-2-methyl-indol-1-yl)-amide
##STR00024##
[0609] Step 1: Following procedures similar to those of Example 1,
step 1, but substituting 5-chloro-2-methylindole for
5-fluoro-2-methylindole, there is prepared
5-chloro-2-methyl-indol-1-ylamine as a solid. MS: 181 (M+H).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.46-7.43 (m, 1H),
7.27-7.24 (m, 1H), 7.12-7.09 (m, 1H), 6.10 (s, 1H), 4.44 (br s,
2H), 2.44-2.43 (m, 3H).
[0610] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg,
1.63 mmol), HOTT (662 mg, 1.78 mmol), and DIPEA (800 .mu.L, 4.58
mmol) in DMF (10 mL) is stirred at rt under N.sub.2 for 10 min.
5-Chloro-2-methyl-indol-1-ylamine (274 mg, 1.52 mmol) is added. The
resulting mixture is stirred at 80.degree. C. overnight. The
mixture is cooled and portioned between EtOAc and water. The
organic phase is separated, washed with saturated aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue is triturated in ether to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-chloro-2-methyl-indol-1-yl)-amide (93 mg, 16%) as a solid. MS:
395 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.83 (s,
1H), 9.27 (s, 1H), 8.33 (d, 1H), 8.20-8.15 (m, 1H), 7.69-7.61 (m,
1H), 7.56 (d, 1H), 7.50-7.43 (m, 2H), 6.36 (s, 1H), 2.78 (s, 3H),
2.37 (s, 3H).
Example 19
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-bromo-indol-1-yl)-amide
##STR00025##
[0612] Step 1: Following procedures similar to those of Example 1,
step 1, but substituting 5-bromoindole for 5-fluoro-2-methylindole,
there is prepared 5-bromoindol-1-ylamine as a solid. MS: 211 (M+H).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.71-7.70 (m, 1H),
7.29-7.28 (m, 2H), 7.13 (d, 1H), 6.32-6.31 (m, 1H), 4.73 (br s,
2H).
[0613] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (596 mg,
2.57 mmol), PyAOP (2.63 mmol), and DIPEA (830 .mu.L, 4.75 mmol) in
DCM (20 mL) is stirred at rt under N.sub.2 for 10 min.
5-Bromoindol-1-ylamine (500 mg, 2.37 mmol) is added. The resulting
mixture is stirred at rt overnight. The mixture is portioned
between EtOAc and water. The organic phase is separated, washed
with saturated aqueous NaHCO.sub.3, water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 2% MeOH in DCM
to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-bromo-indol-1-yl)-amide (246 mg, 24%) as a solid. MS: 425 (M)
& 427 (M+2). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.02
(s, 1H), 9.24 (s, 1H), 8.34 (d, 1H), 8.20-8.15 (m, 1H), 7.84 (d,
1H), 7.68-7.61 (m, 1H), 7.59 (d, 1H), 7.50-7.43 (m, 2H), 7.35 (dd,
1H), 6.57 (dd, 1H), 2.78 (s, 3H).
Example 20
3-Oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid benzyl ester
##STR00026##
[0615] Step 1: Following the procedures described in M. A. Brook,
T. H. Chan Synthesis 1983, (3), 201-204, there is prepared
benzyloxycarbonylamino-acetic acid ethyl ester (95%). MS: 238
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.24-7.41 (m, 5H),
5.20-5.37 (br s, 1H), 5.13 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.96
(br d, J=5.3 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H).
[0616] Step 2: Following the procedures described in P.
Shenbagamurthi, H. A. Smith, J. M. Becker, F. Naider J. Med. Chem.
1986, 29 (5), 802-809; R. K. Olsen J. Org. Chem. 1970, 35 (6),
1912-1915, there is prepared (allyl-benzyloxycarbonyl-amino)-acetic
acid ethyl ester as a liquid (92%): MS: 278 (M+H); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.17-7.41 (m, 5H), 5.70-5.88 (m, 1H),
5.06-5.25 (m, 4H), 4.02-4.23 (m, 2H), 3.81-4.02 (m, 4H), 1.10-1.30
(m, 3H).
[0617] Step 3: To a 0.degree. C. solution of AD-mix-.beta. (2.54 g)
in a mixture of t-butanol (10 mL) and water (12 mL) is added a
solution of (allyl-benzyloxycarbonyl-amino)-acetic acid ethyl ester
(0.52 g, 1.91 mmol) in t-butanol (2.00 mL). The reaction mixture is
allowed to gradually warm to ambient temperature over 2 h, and
stirred at rt for 20 h. Excess oxidant is quenched by the addition
of Na.sub.2SO.sub.3 (2.58 g, 20.44 mmol) and the mixture is stirred
vigorously for 4 h. The mixture is extracted with EtOAc (50 mL) and
the organic phase is washed with saturated aqueous NaCl (2.times.30
mL). The organic solution is dried (MgSO.sub.4), filtered, and
concentrated in vacuo. The residue is purified by silica gel
chromatography (1:1:1 of EtOAc:DCM:heptane to 50:50 DCM:EtOAc
gradient elution) to afford
[benzyloxycarbonyl-(2,3-dihydroxy-propyl)-amino]-acetic acid ethyl
ester as an oil (0.276 g, 46%). MS: 312 (M+H); .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.20-7.40 (m, 5H), 5.05-5.18 (m, 2H),
3.95-4.25 (m, 4H), 3.80-3.95 (m, 1H), 3.20-3.80 (m, 11H), 1.11-1.35
(m, 3H). (See H. Takahata, H. Ouchi, M. Ichinose, H. Nemoto Org.
Lett. 2002, 4 (20), 3459-3462 and supplementary material; J.
Gonzalez, C. Aurigemma, L. Truesdale Org. Synth. 2002, 79,
93-102).
[0618] Step 4: To a solution of
[benzyloxycarbonyl-(2,3-dihydroxy-propyl)-amino]-acetic acid ethyl
ester (1.98 g, 6.37 mmol) in DCM (30 mL) is added
NaIO.sub.4-impregnated silica (13.04 g). The slurry is stirred
rapidly for 4.5 h, and then filtered through a coarse porosity
sintered glass funnel. The filtrate is concentrated to afford
[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-acetic acid ethyl ester
(1.65 g, 92%). MS: 280 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.60-9.68 (m, 1H), 7.26-7.40 (m, 5H), 510-5.19 (m, 2H),
4.00-4.22 (m, 6H), 1.18-1.30 (m, 3H). (see Y.-L. Zhong, T. K. M.
Shing J. Org. Chem. 1997, 62 (8), 2622-2624).
[0619] Step 5: N-Aminophthalimide (0.55 g, 3.4 mmol) is added to a
solution of benzyloxycarbonyl-(2-oxo-ethyl)-amino]-acetic acid
ethyl ester (0.72, 2.6 mmol) in 1,4-dioxane (10 mL), and the
mixture is heated to reflux under N.sub.2 for 15 h. The reaction
mixture is cooled to rt and filtered through diatomaceous earth.
The filtrate is concentrated. The residue is re-dissolved in
CHCl.sub.3 (30 mL) and filtered again through diatomaceous earth.
This filtrate is concentrated to afford
(benzyloxycarbonyl-[2-[(E)-1,3-dioxo-1,3-dihydro-isoindol-2-ylimino]ethyl-
]-amino)-acetic acid ethyl ester (100%). MS: 424 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.77-8.88 (m, 1H), 7.80-7.93 (m, 2H),
7.67-7.80 (m, 2H), 7.23-7.40 (m, 5H), 5.09-5.21 (m, 2H), 4.25-4.45
(m, 2H), 3.97-4.25 (m, 4H), 1.12-1.32 (m, 3H).
[0620] Step 6: A solution of
(benzyloxycarbonyl-{2-[(E)-1,3-dioxo-1,3-dihydro-isoindol-2-ylimino]ethyl-
}-amino)-acetic acid ethyl ester (7.7 mmol) in CH.sub.3CN (65 mL)
is treated with sodium cyanoborohydride (1.92 g, 30.5 mmol), and
acetic acid (6.8 mL, 118.8 mmol) is added with stirring under
N.sub.2. After 5.5 h, the reaction solution is diluted with EtOAc
(150 mL) and washed with saturated aqueous KHCO.sub.3 (3.times.50
mL) and saturated aqueous NaCl (50 mL). The organic phase is dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The residue is
purified by silica gel chromatography (75:25 to 50:50 heptane:ethyl
acetate gradient elution) to afford
{benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylamino)-e-
thyl]-amino}-acetic acid ethyl ester as an oil (2.66 g, 81%). MS:
426 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.79-7.91 (m,
2H), 7.69-7.79 (m, 2H), 7.17-7.39 (m, 5H), 5.04-5.21 (m, 2H),
4.87-5.04 (m, 1H), 4.04-4.23 (m, 4H), 3.48-3.59 (m, 2H), 3.18-3.38
(m, 2H), 1.10-1.30 (m, 3H).
[0621] Step 7: A solution of
{benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylamino)-ethyl]-a-
mino}-acetic acid ethyl ester (0.22 g, 0.52 mmol) in diphenyl ether
(3 mL) is heated to reflux for 2 h. Diphenyl ether is removed by
vacuum distillation and the residue is purified by flash silica gel
chromatography (2:1:1 to 1:1:1 heptane:DCM:EtOAc gradient elution)
to afford
4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxy-
lic acid benzyl ester as a solid (0.126 g, 64%). MS: 380 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.86-7.95 (m, 2H),
7.75-7.86 (m, 2H), 7.24-7.42 (m, 5H), 5.20 (s, 2H), 4.42 (s, 2H),
3.90-4.05 (m, 2H), 3.65-3.87 (m, 2H).
[0622] Step 8: To a solution of benzamidine hydrochloride hydrate
(2 mmol) in anhydrous DMF (4 mL) is added sodium salt of
2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (0.46 g, 2.32
mmol) and the reaction mixture heated at 100.degree. C. under N2
for 1 hour. The reaction is cooled to rt and water (15 mL) is
added. After addition of water, immediate precipitation of the
product is observed. The solids are collected by filtration, washed
with water (2.5 mL) and vacuum dried to yield
2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%).
(see: P. Zhichkin, D. J. Fairfax, S. A. Eisenbeis, Synthesis, 2002,
720-722.)
[0623] Step 9: A solution of 2-phenyl-pyrimidine-5-carboxylic acid
methyl ester (3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF
and water (1:1:1 in volume, 120 mL) is stirred at rt overnight.
MeOH and THF are evaporated off to give an aqueous solution. The
aqueous solution is acidified with 5% hydrochloric acid to adjust
pH to between 2.5 and 3. The precipitate is filtered off and washed
with water, dried in vacuo to yield 2.94 g (.about.100%) of
2-phenyl-pyrimidine-5-carboxylic acid as a solid. MS: 201
(M+H).
[0624] Step 10: A solution of
4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxylic
acid benzyl ester (53 mg, 0.14 mmol) in MeOH (10 mL) is treated
with anhydrous hydrazine (0.3 mL, 9.56 mmol). The reaction mixture
is stirred at reflux under N.sub.2 for 3.5 h. The reaction mixture
is concentrated. The residue is dissolved in a mixture of DMF (2
mL) and DCM (2 mL), and treated with 2-phenyl-pyrimidine-5-carbonyl
chloride (32 mg, 0.15 mmol). The mixture is stirred under N.sub.2
for 16 h, and then diluted with EtOAc (35 mL). The mixture is
washed successively with saturated aqueous KHCO.sub.3, (15 mL),
water (2.times.15 mL), and saturated aqueous NaCl (15 mL), dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The residue is
purified by flash silica gel chromatography (80:20 to 0:100
heptane:EtOAc gradient elution) to afford
3-oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid benzyl ester as an oil (111 mg, 18%). MS: 432 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 9.70-10.10 (br, 1H), 9.06 (s,
2H), 8.46 (dd, J=7.8, 1.7 Hz, 2H), 7.44-7.60 (m, 3H), 7.25-7.40 (m,
5H), 5.18 (s, 2H), 4.36 (s, 2H), 3.93 (t, J=5.1 Hz, 2H), 3.69-3.81
(br s, 2H). IC.sub.50=103.5 nM.
Example 21
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoro-indol-1-yl)amide
##STR00027##
[0626] Step 1: A solution of 5-fluoroindole (5.4 g) and
toluene-4-sulphonyl chloride (9.12 g) in toluene (300 mL) is
treated with a cooled solution of sodium hydroxide pellets (23.2 g)
in water (200 mL) followed by the tetrabutylammonium hydrogen
sulfate catalyst (400 mg). The mixture is stirred at rt for 24 h.
The organic phase is separated, washed with water and brine, dried
(MgSO.sub.4) and concentrated in vacuo to afford
5-fluoro-1-(toluene-4-sulfonyl)-1H-indole (10.7 g, 78%). MS: 290
(M+H)
[0627] Step 2: A solution of 5-fluoro-1-(toluene-4-sulfonyl)indole
(5.2 g) in dry CH.sub.3CN (80 mL) is cooled in an ice-bath and
treated drop wise with chlorosulfonic acid (12 mL). The reaction
mixture is allowed to warm to rt and stirred for 24 h. The reaction
mixture is carefully poured onto ice/water (300 mL). The
precipitate is collected by filtration and washed with water to
afford 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole
(6.8 g, 98%) as a solid. MS: 386 (M-H).
[0628] Step 3: A solution of
5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)indole (2.52 g) in
DCM (75 mL) is added to an aqueous solution of dimethylamine (40%,
20 mL) in water (50 mL) and stirred at rt for 20 h. The organic
phase is separated, washed with water, brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to afford
5-fluoro-1-(toluene-4-sulfonyl)-1H-indole-3-sulphonic acid
dimethylamide (2.55 g, 99%) as a solid. MS: 397 (M+H).
[0629] Step 4: A mixture of
5-fluoro-1-(touene-4-sulfonyl)indole-3-sulfonic acid dimethylamide
(2.55 g) in MeOH (100 mL) and 5 N KOH (15 mL) is heated to reflux
for 1.5 hours. The reaction mixture is concentrated in vacuo. The
residue is diluted with water (50 mL) and acidified to pH 3 with 10
N aqueous HCl. The mixture is extracted with EtOAc. The organic
layer is separated, washed with water, brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to afford
5-fluoro-1H-indole-3-sulfonic acid dimethylamide (1.35 g, 87%) as a
solid. MS: 241 (M-H).
[0630] Step 5: A solution of 5-fluoro-1H-indole-3-sulfonic acid
dimethylamide (1.24 g) in dry DMF (50 mL) is cooled to 0.degree. C.
and treated portion wise with 60% MaH oil dispersion (3.07 g). The
mixture is stirred at 0.degree. C. for 30 min.
Hydroxylamine-O-sulfonic acid (2.9 g) is added portion wise and the
mixture is warmed to rt and stirred for 5 h. The reaction mixture
is poured onto ice/water and extracted with EtOAc. The organic
layer is separated, washed water and brine, dried (MgSO.sub.4)
filtered and concentrated in vacuo. The residue is triturated with
ether. The solid is collected by filteration to afford
1-amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide (0.53 g,
41%). MS: 258 (M+H).
[0631] Step 6: A suspension of
2-(3-fluorophenyl)-pyrimidine-5-carboxylic acid (76 mg) in dry DCM
(25 mL)/dry DMF (2 drops) is treated with oxalyl chloride (0.15 mL)
and stirred at rt for 3.5 hours. The reaction mixture is
concentrated in vacuo. The residue is dissolved in toluene (15 mL)
and then concentrated in vacuo. The residue is dried on high vacuum
pump, and then dissolved in EtOAc (7 mL). The solution is added to
a mixture of 1-amino-5-fluoro-1H-indole-3-sulfonic acid
dimethylamide (100 mg) and Na.sub.2CO.sub.3 (106 mg) in EtOAc (5
mL)/water (5 mL). The mixture is stirred at rt for 24 h. The
organic phase is separated, washed water and brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 50% EtOAc in
heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide (100 mg, 62%) as
a solid. MS: 458 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 2.67 (s, 6H), 7.20-7.3 (m, 1H), 7.45-7.55 (m, 1H), 7.57-7.6
(dd, 1H), 7.65-7.75 (m, 2H), 8.2 (d, 1H), 8.38-8.4 (d, 2H), 9.45
(s, 2H), 12.6 (s, 1H).
Example 22
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide
##STR00028##
[0633] A solution of
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (116 mg)
and HATU (190 mg) in dry DMF is treated with DIPEA (0.09 mL) and
stirred at rt for 40 min. 1-Amino-5-fluoro-1H-indole-3-sulfonic
acid dimethylamide (192 mg) is added and the mixture is stirred at
rt for 24 h. The mixture is concentrated in vacuo. The residue is
dissolved in EtOAc, washed with 2 N aqueous NaOH, water and brine,
dried (MgSO.sub.4) and concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 30%
EtOAc/heptane to afford
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(3-dimethylsulfamoyl-5-fluoroindol-1-yl)amide (85 mg, 40%) as
a solid. MS: 472 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 2.68 (s, 6H), 2.79 (s, 3H), 7.25-7.35 (m, 1H), 7.45-7.55
(m, 1H), 7.57-7.80 (m, 3H), 8.20 (d, 1H), 8.35 (s, 1H), 8.47 (s,
2H), 9.28 (s, 1H), 12.40 (s, 1H).
Example 23
2-(3-Fluorophenyl)pyrimidine-5-carboxylicacid-[5-fluoro-3-(morpholine-4-su-
lfonyl)indol-1-yl]amide
##STR00029##
[0635] Step 1: A solution of
5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (1 g) in
DCM is added to a solution of morpholine (2.26 mL) in water (50 mL)
and stirred at rt for 5 h. The organic phase is separated and
washed water, brine and dried (MgSO.sub.4), filtered and
concentrated in vacuo to afford
5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indol-
e (1.3 g, 100%). MS: 439 (M+H).
[0636] Step 2: A solution of
5-fluoro-3-(morpholine-4-sulfonyl)-1-(toluene-4-sulfonyl)-1H-indole
(1.3 g) in MeOH (50 mL)/5 N KOH (3 mL) is heated to reflux for 1 h.
The reaction mixture is concentrated in vacuo. The residue is
diluted with water (30 mL) and acidified with 10 N aqueous HCl to
pH 4. The mixture is extracted with EtOAc. The organic layer washed
with water, brine and dried (MgSO.sub.4), filtered and concentrated
in vacuo to afford 5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole
(0.8 g, 95%) as a solid. MS: 285 (M+H).
[0637] Step 3: Following procedures similar to those of Example 21,
step 5, but substituting
5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole for
5-fluoro-1H-indole-3-sulfonic acid dimethylamide, and the product
is purified by silica gel chromatography eluting with 20% EtOAc,
there is prepared
1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole (16%) as a
solid. MS: 300 (M+H).
[0638] Step 4: Following procedures similar to those of Example 21,
step 6, but substituting
1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole for
1-amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide, there is
prepared
2-(3-fluorophenyl)pyrimidine-5-carboxylicacid-[5-fluoro-3-(morph-
oline-4-sulfonyl)indol-1-yl]amide (27%) as a solid. MS: 500 (M+H).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.95 (m, 4H), 3.67 (m,
4H), 7.25-7.35 (m, 1H), 7.45-7.55 (m, 1H), 7.57-7.60 (dd, 1H),
7.62-7.72 (q, 1H), 7.75-7.80 (q, 1H), 8.20 (d, 1H), 8.35-8.40 (d,
1H), 8.41 (s, 1H), 9.45 (s, 2H), 12.6 (s, 1H).
Example 24
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(morpholine-4-sulfonyl) indol-1-yl]amide
##STR00030##
[0640] Following procedures similar to those of Example 22, but
substituting 1-amino-5-fluoro-3-(morpholine-4-sulfonyl)-1H-indole
for 1-amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide, there
is prepared 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(morpholine-4-sulfonyl)indol-1-yl]amide (48%) as a
solid. MS: 512 (M-H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
2.80 (s, 3H), 2.95 (m, 4H), 3.67 (m, 4H), 7.25-7.35 (m, 1H),
7.45-7.55 (m, 1H), 7.57-7.60 (m, 1H), 7.62-7.72 (m, 1H), 7.75-7.80
(m, 1H), 8.15-8.20 (d, 1H), 8.30-8.35 (d, 1H), 8.45 (s, 1H), 9.30
(s, 1H), 12.4 (s, 1H).
Example 25
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-sulfamoylindol-1-yl)amide
##STR00031##
[0642] Step 1: A solution of
2-(3-fluorophenyl)pyrimidine-5-carboxylic
acid-(5-fluoroindol-1-yl)amide (0.35 g,) in dry CH.sub.3CN (20 mL)
is treated with chlorosulfonic acid (0.5 mL) and stirred at rt for
24 h. The reaction mixture is poured onto ice/water (150 mL) and
extracted with EtOAc. The organic layer is washed with water, brine
and dried (MgSO.sub.4), filtered and concentrated in vacuo to
afford
5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-s-
ulfonyl chloride (0.43 g, 95%). MS: 449 (M+H).
[0643] Step 2: A solution of
5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-s-
ulfonyl chloride (0.14 g) in DCM (20 mL) is treated with a solution
of aqueous ammonia solution (28%-5 mL) in water (15 mL) and stirred
at rt for 24 h. The reaction mixture is acidified with 10 N aqueous
HCl to pH 3 and extracted with DCM. The organic layer is washed
with water and brine, dried (MgSO.sub.4), filtered and concentrated
in vacuo. The residue is purified by silica gel chromatography
eluting with 50% EtOAc in heptane to afford
2-(3-fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-sulfamoylindol-1-yl)amide (10 mg, 8%) as a solid.
MS: 430 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
7.20-7.30 (m, 1H), 7.40-7.50 (m, 2H), 7.60-7.72 (m, 2H), 8.10 (s,
1H), 8.19-8.22 (d, 1H), 8.33-8.37 (d, 1H), 9.44 (s, 1H), 12.45 (s,
1H).
Example 26
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide
##STR00032##
[0645] Following procedures similar to those of Example 25, but
substituting 40% aqueous methylamine for aqueous ammonia solution,
there is prepared 2-(3-fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide (60%) as a solid.
MS: 444 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.45
(d, 3H), 7.20-7.30 (m, 1H), 7.40-7.50 (m, 2H), 7.60-7.70 (m, 3H),
8.19-8.22 (d, 1H), 8.24 (s, 1H), 8.34-8.37 (d, 1H), 9.44 (s, 1H),
12.50 (s, 1H).
Example 27
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide
##STR00033##
[0647] Following procedures similar to those of Example 25, but
substituting an aqueous solution of 2-(morpholin-4-yl)ethylamine
for the aqueous ammonia solution, there is prepared
2-(3-fluorophenylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide
(35%). MS: 543 (M+H). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
2.20-2.38 (m, 6H), 2.89-2.95 (q, 2H), 3.40-3.50 (s, 4H), 7.20-7.30
(m, 1H), 7.42-7.55 (m, 2H), 7.63-7.70 (m, 3H), 8.19-8.22 (d, 1H),
8.26 (s, 1H), 8.34-8.37 (d, 1H), 9.44 (s, 2H), 12.40-12.60 (s,
1H).
Example 28
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide
##STR00034##
[0649] Step 1: A solution
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(5-fluoroindol-1-yl)amide (1 g, 2.75 mmol) in dry CH.sub.3CN
is cooled to 0.degree. C. and treated drop wise with chlorosulfonic
acid (0.55 mL) and stirred for 2 hours. The precipitated solid is
filtered off and washed with ether to afford
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylperimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonic acid (1.06 g, 87%) as an off-white solid. MS: 443
(MH-).
[0650] Step 2: To a suspension of
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonic acid (1.06 g) in DCM (60 mL) at 0.degree. C. is
added dry DMF (10 drops). Oxalyl chloride (1.05 mL) is added drop
wise and the mixture is stirred at 0.degree. C. for 3 h. The
mixture is filtered and the collected solid is washed with ether to
afford
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonyl chloride (0.94 g). MS: 461 (M-H)
[0651] Step 3: Following procedures similar to those of Example 25,
step 2, but substituting 40% aqueous methylamine for the aqueous
ammonia solution, and substituting
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonyl chloride for
5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-s-
ulfonyl chloride, there is prepared
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-methylsulfamoyl)indol-1-yl)amide (40 mg, 35%) as a
solid. MS: 456 (M-H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
2.45 (d, 3H), 2.80 (s, 3H), 7.20-7.30 (m, 1H), 7.40-7.50 (m, 2H),
7.60-7.70 (m, 3H), 8.17-8.20 (d, 1H), 8.30-8.35 (d, 2H), 9.28 (s,
1H), 12.30 (s, 1H).
Example 29
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide
##STR00035##
[0653] Following procedures similar to those of Example 25, step 2,
but substituting an aqueous solution of
4-aminomethyltetrahydropyran for the aqueous ammonia solution, and
substituting
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonyl chloride for
5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-s-
ulfonyl chloride, there is prepared
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-{5-fluoro-[(3-tetrahydropyran-4-ylmethyl)sulfamoyl]indol-1-yl}amide
as a solid. MS: 542 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 1.00-1.15, (m, 2H), 1.50-1.70, (m, 3H), 2.60-2.70, (t, 2H),
2.80, (s, 1H), 3.1-3.2, (t, 2H), 3.70-3.80, (dd, 2H), 7.20-7.30,
(m, 1H), 7.40-7.50, (m, 1H), 7.60-7.70, (m, 4H), 8.16-8.20, (d,
1H), 8.28-8.34 (d, 2H), 9.28, (s, 1H), 12.25, (s, 1H).
Example 30
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide
##STR00036##
[0655] Following procedures similar to those of Example 25, step 2,
but substituting an aqueous solution of
2-(morpholin-4-yl)ethylamine for the aqueous ammonia solution, and
substituting
5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-i-
ndole-3-sulfonyl chloride for
5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-s-
ulfonyl chloride, there is prepared
2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-[5-fluoro-3-(2-morpholin-4-ylethylsulfamoyl)indol-1-yl)amide
(58%) MS: 557 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
2.20-2.30 (s, 4H), 2.30-2.40 (t, 2H), 2.80 (s, 3H), 2.89-2.95 (q,
2H), 3.40-3.50 (s, 4H), 7.20-7.30 (m, 1H), 7.42-7.55 (m, 2H),
7.63-7.70 (m, 3H), 8.17-8.20 (d, 1H), 8.32-8.35 (d, 2H), 9.28 (s,
2H), 12.25-12.30 (s, 1H).
Example 31
2-(3-Fluorophenyl)pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide
##STR00037##
[0657] Step 1: The crude product of 1-amino-4-fluoroindole is
prepared according to the procedures described in J. Hymes et al.,
J.O.C., (2004), 69, 1368-1371. The crude product is then purified
by silica gel chromatography eluting with 30% DCM in heptane to
afford 1-amino-4-fluoroindole (43%). MS: 151 (M+H).
[0658] Step 2: A solution of
2-(3-fluorophenyl)-pyrimidine-5-carboxylic acid (0.33 g), HATU
(0.67 g) and hydroxyazabenzotriazole (0.26 g) in dry DMF (15 mL) is
stirred at rt for 30 min under N.sub.2. A solution of
1-amino-4-fluoroindole (0.24 g) in dry DMF (5 mL) is added followed
by the addition of DIPEA (0.39 mL). The mixture is stirred at
80.degree. C. for 24 h, cooled to rt, and then concentrated in
vacuo. The residue is dissolved in EtOAc and washed with water,
brine and dried (MgSO.sub.4), filtered and concentrated in vacuo.
The residue is purified by silica gel chromatography eluting with
60% DCM/heptane to afford 2-(3-fluorophenyl)pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide (0.24 g, 53%) as a solid. MS: 351
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 6.64 (d, 1H),
6.89-6.92 (q, 1H), 7.15-7.22 (m, 1H), 7.31-7.33 (d, 1H), 7.46-7.52
(m, 1H), 7.56 (d, 1H), 7.63-7.70 (q, 1H), 8.18-8.23 (d, 1H),
8.34-8.37 (d, 1H), 9.45 (s, 2H), 12.30 (s, 1H). IC.sub.50=11
nM.
Example 32
2-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide
##STR00038##
[0660] Following procedures similar to those of Example 31, step 2,
but substituting 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid for 2-(3-fluorophenyl)-pyrimidine-5-carboxylic acid, there is
prepared 2-(3-fluorophenyl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide (63%) as a solid. MS: 365 (M-H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.75 (6, 3H), 6.61 (d,
1H), 6.86-6.92 (q, 1H), 7.15-7.22 (m, 1H), 7.30-7.32 (d, 1H),
7.40-7.46 (m, 1H), 7.56-7.65 (m, 2H), 8.13-8.16 (d, 1H), 8.28-8.31
(d, 1H), 9.21 (s, 1H), 12.05 (s, 1H).
Example 33
2-(Pyridin-2-yl)-pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide
##STR00039##
[0662] A suspension of 2-(pyridine-2-yl)-pyrimidine-5-carbonyl
chloride (0.44 g) in EtOAc (20 mL) is added portion wise to a
mixture of 1-amino-4-fluoroindole (0.30 g) and K.sub.2CO.sub.3
(0.276 g) in EtOAc (10 mL)/water (20 mL) and the resulting mixture
is stirred at rt for 24 h. The aqueous phase is separated and
extracted twice with EtOAc. The combined organic layer is washed
with water and brine, dried (MgSO.sub.4), filtered and
concentration in vacuo. The residue is purified by silica gel
chromatography eluting with EtOAc to afford
2-(pyridin-2-yl)pyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide (0.115 g, 17%) as a solid. MS: 334
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 6.65 (d, 1H),
6.89-6.95 (q, 1H), 7.16-7.23 (m, 1H), 7.32-7.35 (d, 1H), 7.57 (d,
1H), 7.57-7.64 (m, 1H), 8.02-8.08 (t, 1H), 8.50-8.52 (d, 1H),
8.82-8.83 (d, 1H), 9.49 (s, 2H), 12.30 (s, 1H).
Example 34
2-(Pyridin-2-yl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide
##STR00040##
[0664] A solution of
2-(pyridine-2-yl)-4-methylpyrimidine-5-carboxylic acid (0.11 g) and
HATU (0.19 g) in dry DMF (7 mL) is treated with DIPEA (0.09 mL) and
stirred at rt under N.sub.2 for 30 min. 1-Amino-4-fluoroindole
(0.112 g) is added and the mixture is stirred at rt for 24 h. The
mixture is concentrated in vacuo. The residue is dissolved in
EtOAc, washed with water and brine and dried (MgSO.sub.4),
filtered, and concentration in vacuo. The residue is purified by
silica gel chromatography eluting with 75% EtOAc to afford
2-(pyridin-2-yl)-4-methylpyrimidine-5-carboxylic
acid-(4-fluoroindol-1-yl)amide (0.085 gms, 50%). MS: 348 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.82 (s, 3H), 6.65 (d,
1H), 6.93-6.97 (q, 1H), 7.19-7.26 (m, 1H), 7.35-7.38 (d, 1H), 7.62
(d, 1H), 7.74-7.78 (m, 1H), 8.20-8.25 (t, 1H), 8.58-8.61 (d, 1H),
8.85-8.86 (d, 1H), 9.33 (s, 1H), 12.15 (s, 1H).
Example 35
2-Phenyl-pyrimidine-5-carboxylic acid
[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide
##STR00041##
[0666] Step 1: Following procedures described in F. Chau, J.-C.
Malanda, and R. Milcent J. Heterocyclic Chem. 1997, 34, 1603-1606,
there is prepared 5-methyl-3H-1,3,4-oxadiazol-2-one (24%). MS: 101
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.76 (br s, 1H),
2.28 (s, 3H).
[0667] Step 2: To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-one
(2.77 g, 27.7 mmol) in MeOH (25 mL) is added 25 wt % NaOMe solution
in methanol (6.4 mL, 27.9 mmol) and the mixture is stirred at rt
for 10 min. The mixture is concentrated in vacuo and the residue is
added to a solution of 2-chloro-4'-fluoroacetophenone (4.71 g, 27.3
mmol) and tetrabutylammonium bromide (0.174 g, 0.54 mmol) in
CHCl.sub.3 (16 mL). The mixture is heated to reflux for 2.5 h under
N.sub.2. The reaction mixture is then allowed to cool and stirred
overnight at ambient temperature. The resultant slurry is filtered
through qualitative filter paper and the filtrate is concentrated
to obtain a liquid. This liquid is further filtered through a pad
of silica gel, eluting with 1:1 EtOAc/DCM. The filtrate is
concentrated in vacuo to afford
3-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-5-methyl-3H-1,3,4-oxadiazol-2-one
(100%). MS: 237 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.90-8.10 (m, 2H), 7.10-7.22 (m, 2H), 5.08 (s, 2H), 2.29 (s,
3H).
[0668] Step 3: To a solution of
3-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-5-methyl-3H-1,3,4-oxadiazol-2-one
(2.3 g, 9.7 mmol) in a mixture of 2-propanol (12 mL) and water (0.3
mL) is added hydrzazine monohydrate (0.71 mL, 14.6 mmol). The
reaction mixture is heated to reflux under N.sub.2 for 14.5 h, and
then a solution of oxalic acid (0.3 g, 3.3 mmol) in 2-propanol (6
mL) is added. The resulting precipitate is removed by filtration.
The filtrate is concentrated to 35 mL and then chilled to afford
N-[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-acetamide
as a crystal that is collected by filtration (0.83 g, 34%). MS: 251
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H),
10.16 (s, 1H), 7.65-7.79 (m, 2H), 7.16-7.27 (m, 2H), 4.57 (s, 2H),
1.90 (s, 3H).
[0669] Step 4: To a slurry of
N-[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-acetamide
(0.48 g, 1.9 mmol) in MeOH (5 mL) is added 37% aqueous HCl. The
mixture is heated to reflux for 3 h, and then cooled to rt. The
mixture is basified with 1 M aqueous NaOH to pH 12. The resulting
precipitate is collected by filtration and dried to afford
4-amino-6-(4-fluoro-phenyl)-4,5-dihydro-2H-1,2,4-triazin-3-one
(0.35 g, 88%). MS: 209 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 10.17 (s, 1H), 7.67-7.75 (m, 2H), 7.18-7.29 (m, 2H), 4.75
(s, 2H), 4.45 (s, 2H).
[0670] Step 5: To a slurry of
4-amino-6-(4-fluoro-phenyl)-4,5-dihydro-2H-1,2,4-triazin-3-one
(0.26 g, 1.23 mmol), 2-phenyl-pyrimidine-5-carboxylic acid (0.25 g,
1.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (0.37 g, 1.94 mmol) in DMF (12 mL) is added Et.sub.3N
(0.2 mL, 1.435 mmol) under N.sub.2 and the reaction mixture is
stirred at rt for 49 h. The mixture is diluted with EtOAc (120 mL),
and washed successively with saturated aqueous NH.sub.4Cl
(2.times.50 mL), water (2.times.50 mL), and saturated aqueous NaCl
(50 mL). The organic phase is dried (MgSO.sub.4), filtered, and
concentrated in vacuo. The residue is triturated with EtOH (30 mL)
to afford 2-phenyl-pyrimidine-5-carboxylic acid
[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-amide
(0.12 g, 25%). MS: 391 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.25 (s, 1H), 10.58 (s, 1H), 9.31 (s, 2H), 8.47 (dd,
J=7.7, 1.8 Hz, 2H), 7.70-7.86 (m, 2H), 7.49-7.67 (m, 3H), 7.18-7.34
(m, 2H), 4.77.
Example 36
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide
##STR00042##
[0672] To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid (0.28 g, 1.4 mmol) in anhydrous DCM (10 mL) at 0.degree. C. is
added the oxalyl chloride (0.18 mL, 1.4 mmol) followed by the
addition of DMF (0.11 mL). The mixture is stirred at 0.degree. C.
for 30 min, and then allowed to warm up to rt and stirred for 30
min. The mixture is concentrated in vacuo. The residue is dissolved
in anhydrous DCM (10 mL). 2-(4-Amino-piperazin-1-yl)-ethanol (0.145
g, 1 mmol) is added at rt followed by the addition of NMP (0.19 mL,
2 mmol). The mixture is stirred at rt for 2 h and the mixture is
then concentrated in vacuo. The residue is triturated in Et.sub.2O
and the resulting solid is collected by filtration to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide (0.16 g). MS: 346
(M+H).
Example 37
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00043##
[0674] To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid (0.317 g, 1.45 mmol) in anhydrous DMF (5 mL) is added
4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (0.206 g, 1.45
mmol) followed by the addition of DMTMM (0.421 g, 1.52 mmol). The
mixture is stirred at rt overnight. The mixture is partitioned
between a saturated aqueous NaHCO.sub.3 solution and EtOAc. The
organic phase is separated, dried (MgSO.sub.4), filtered and
concentrated in vacuo to afford
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (0.306 g)
as a solid. MS: 329 (M+H).
Example 38
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic
acid[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide
##STR00044##
[0676] Step 1: A solution of (5-fluoro-1H-indol-3-yl)-acetic acid
(1 g, 5.2 mmol) in MeOH (20 mL) is treated with sulfuric acid (20
.mu.L) and stirred at rt for 1 h. This mixture is treated with 10%
aqueous NaHCO.sub.3 (200 .mu.L) and then concentrated in vacuo to
afford (5-fluoro-1H-indol-3-yl)-acetic acid methyl ester, which is
used in the next step without further purification. MS: 208 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.68 (s, 3H), 3.72 (s,
2H), 6.86 (m, 1H), 7.16 (m, 1H), 7.21 (s, 1H), 7.28 (m, 1H).
[0677] Step 2: The above (5-fluoro-1H-indol-3-yl)-acetic acid
methyl ester is dissolved in THF (40 mL), cooled to 0.degree. C.,
and treated with MeMgBr (18.5 mL, 26 mmol, 1.4 M in PhMe/THF
(3:1)). The mixture is stirred at rt for 12 h. Additional MeMgBr (5
mL, 7 mmol) is added and the mixture is stirred at rt for 6 h. The
mixture is poured onto ice/water, extracted with EtOAc (100 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with
20%-70% EtOAc in heptane to afford
1-(5-fluoro-1H-indol-3-yl)-2-methyl-propan-2-ol (0.65 g, 60%). MS:
208 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.28 (s, 6H),
2.87 (s, 2H), 6.94 (m, 1H), 7.14 (m, 1H), 7.26-7.30 (m, 2H).
[0678] Step 3: A solution of
1-(5-fluoro-1H-indol-3-yl)-2-methyl-propan-2-ol (207 mg, 1 mmol) in
DMF (10 mL) is cooled to 0.degree. C., treated with NaH (600 mg, 15
mmol, 60% in mineral oil) and stirred for 30 min.
H.sub.2NOSO.sub.3H (565 mg, 5 mmol) is added portion wise, and the
mixture is warmed to rt over 2 h. The mixture is diluted with EtOAc
(100 mL), quenched with water, extracted with EtOAc, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol, which is used
in the next step without further purification.
[0679] Step 4: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (175 mg, 0.8 mmol)
in DCM (5 mL) is treated with DMF (20 .mu.L) and ClCOCOCl (348
.mu.L, 4 mmol), and stirred at rt for 3 h. Toluene (10 mL) is added
and the mixture is concentrated in vacuo. The residue is added to a
solution of the above
1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol and
Na.sub.2CO.sub.3 (1 g) in EtOAc/H.sub.2O (20 mL, 1:1). The mixture
is stirred at rt for 12 h. The mixture is then diluted with
saturated aqueous Na.sub.2CO.sub.3, extracted with EtOAc. The
organic layer is separated, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 30%-50% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (160
mg, 50%). MS: 423 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 1.14 (s, 6H), 2.77 (s, 2H), 7.03 (m, 1H), 7.33 (s, 1H),
7.35-7.55 (m, 3H), 7.65 (m, 1H), 8.21 (m, 1H), 8.36 (m, 1H), 9.43
(s, 2H).
Example 39
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide
##STR00045##
[0681] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (250 mg,
1.07 mmol) in DCM (10 mL) is cooled to 0.degree. C., treated with
DMF (20 .mu.L) and ClCOCOCl (280 .mu.L, 3.21 mmol), and stirred for
20 min. Toluene (10 mL) is added and the mixture is concentrated in
vacuo. The residue is dissolved in pyridine (10 mL) and treated
with DMAP (5 mg) and
1-(1-amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol (0.72 mmol).
The mixture is stirred at rt for 12 h. The mixture is diluted with
saturated aqueous Na.sub.2CO.sub.3, extracted with EtOAc. The
organic layer is separated, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 20%-60% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (218 mg,
70%). MS: 437 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
1.14 (s, 6H), 2.77 (s, 2H), 3.29 (s, 3H), 7.03 (m, 1H), 7.37 (s,
1H), 7.35-7.55 (m, 3H), 7.65 (m, 1H), 8.19 (m, 1H), 8.34 (m, 1H),
9.22 (s, 1H).
Example 40
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide
##STR00046##
[0683] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (748 mg, 3.48
mmol) in DMF (30 mL) is treated with HATU (1.3 g, 3.48 mmol) and
DIPEA (1.2 mL, 6.96 mmol), and the mixture is stirred at rt for 30
min. 1-(1-Amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol (2.9 mmol)
is added and the mixture is stirred at 80.degree. C. for 12 h. The
mixture is diluted with EtOAc, washed with saturated aqueous
NH.sub.4Cl and saturated aqueous Na.sub.2CO.sub.3, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (990 mg,
81%). MS: 420 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
1.13 (s, 6H), 2.75 (s, 2H), 2.85 (s, 3H), 6.84 (m, 1H), 7.24 (m,
1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.95 (s, 1H), 7.98 (m, 1H), 8.44
(m, 1H), 8.76 (m, 1H), 9.15 (s, 1H).
Example 41
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyano-5-fluoro-indol-1-yl)-amide
##STR00047##
[0685] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in THF (8 mL) is
cooled to 0.degree. C., treated with chlorosulfonyl isocyanate (86
.mu.L, 0.99 mmol) and the mixture is stirred at rt for 1 h. The
mixture is treated with Et.sub.3N (138 .mu.L, 0.99 mmol) and
stirred for 1 h. The mixture is diluted with brine, extracted with
EtOAc. The organic layer is separated, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 25% -35% EtOAc in heptane to
afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 38%). MS: 390 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.78 (s, 3H), 7.32 (m,
1H), 7.46 (m, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.77 (m, 1H), 8.20
(m, 1H), 8.35 (m, 1H), 8.65 (s, 1H), 9.28 (s, 1H).
Example 42
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide
##STR00048##
[0687] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 0.31 mmol), TMSN.sub.3
(62 .mu.L, 0.465 mmol), and TBAF (0.155 .mu.L, 0.155 mmol, 1 M in
THF) in toluene (3 mL) is heated at 80.degree. C. for 18 h. The
mixture is cooled, diluted with EtOAc, and washed with 1 M HCl. The
organic layer is extracted with Na.sub.2CO.sub.3. The aqueous layer
is acidified to pH 3 with 3 N aqueous HCl, extracted with EtOAc The
organic layer is separated, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide (100 mg, 75%). MS:
433 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.81 (s,
3H), 7.28 (m, 1H), 7.47 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 8.01
(m, 1H), 8.21 (m, 1H), 8.33 (m, 1H), 8.36 (s, 1H), 9.33 (s, 1H).
IC.sub.50=5 nM.
Example 43
2-Phenyl-pyrimidine-5-carboxylic acid [1,2,4]triazol-4-ylamide
##STR00049##
[0689] To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (300
mg, 1.5 mmol) in DCM (10 mL) is added
1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (316 mg, 1.65 mmol)
and N-hydroxybenzotriazole (223 mg, 1.65 mmol) at rt and the
mixture is stirred for 10 min. 4-Amino-4H-1,2,4-triazole (252 mg, 3
mmol) is added and the mixture is stirred at rt for 3 days. The
resulting precipitate is filtered, washed with DCM and water, and
dried in vacuum oven at 40.degree. C. overnight to afford
2-phenyl-pyrimidine-5-carboxylic acid [1,2,4]triazol-4-ylamide (270
mg) as a solid. MS: 267 (M+H); .sup.1H NMR (300 MHz, DMSO):
.delta.=7.59 (m, 3H), 8.50 (d, 2H), 8.84 (s, 2H), 9.36 (s, 2H).
IC.sub.50=262.5 nM.
Example 44
2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-Ylamide
##STR00050##
[0691] Method A: To a solution of 2-phenyl-pyrimidine-5-carboxylic
acid (150 mg, 075 mmol) in DCM (10 mL) is added
1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (158 mg, 0.83 mmol)
and N-hydroxybenzotriazole (112 mg, 0.83 mmol) at rt and the
mixture is stirred for 10 min. 1-Aminopiperidine (150 mg, 1.5 mmol)
is added. The mixture is stirred at rt overnight. The mixture is
washed with 2 N aqueous HCl (5 mL), saturated aqueous NaHCO.sub.3,
(5 mL), and water (5 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 10% EtOAc in heptane to afford
2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-ylamide (125 mg)
as a solid. MS: 290 (M+H).
[0692] Method B: Following procedures similar to those of Example
127 but substituting piperadin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid piperadin-1-yl-amide (72%) as a solid. MS: 283 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 1.35-1.98 (m, 6H), 2.20-3.60 (m,
4H), 6.60-7.17 (d, N--H), 7.52 (s, 3H), 8.52 (s, 2H), 9.07-9.39 (d,
2H).
Example 45
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-fluoro-phenyl)-hydrazide
##STR00051##
[0694] Following procedures similar to those of Example 44, but
substituting (2-fluoro-phenyl)-hydrazine for 1-aminopiperidine,
there is prepared 2-phenyl-pyrimidine-5-carboxylic acid
N'-(2-fluoro-phenyl)-hydrazide as a solid. MS: 309 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 6.68 (broad, 1H), 6.87 (m, 1H),
7.04 (m, 3H), 7.51 (m, 3H), 8.51 (m, 2H), 9.36 (s, 2H), 10.65
(broad, 1H). IC.sub.50=12 nM.
Example 46
2-Phenyl-pyrimidine-5-carboxylic acid
N'-ethyl-N'-tolyl-hydrazide
##STR00052##
[0696] Following procedures similar to those of Example 44, but
substituting N-ethyl-N-para-tolyl-hydrazine for 1-aminopiperidine,
there is prepared 2-phenyl-pyrimidine-5-carboxylic acid
N'-ethyl-N'-tolyl-hydrazide as a solid. MS: 333 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta.=0.87 (t, 1H), 1.11 (t, 2H), 1.28 (t,
3H), 2.28 (d, 3H), 3.46 (q, 1H), 3.65 (q, 1H), 6.84 (d, 1H), 6.94
(d, 1H), 7.10 (t, 2H), 7.52 (m, 3H), 8.47 (m, 2H), 9.12 (s, 1H0,
9.23 (s, 1H).
Example 47
2-Phenyl-pyrimidine-5-carboxylic acid
(3-oxo-morpholin-4-yl)-amide
##STR00053##
[0698] Following procedures similar to those of Example 44, but
substituting 4-amino-morpholin-3-one for 1-aminopiperidine, there
is prepared 2-phenyl-pyrimidine-5-carboxylic acid
(3-oxo-morpholin-4-yl)-amide as a solid. MS: 299 (M+H); .sup.1H NMR
(300 MHz, DMSO): .delta.=3.66 (m, 2H), 4.00 (m, 2H), 4.26 (s, 2H),
7.60 (m, 3H), 8.47 (m, 2H), 9.29 (s, 2H), 11.27 (s, 1H).
IC.sub.50=55 nM.
Example 48
2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide
##STR00054##
[0700] Step 1: To a solution of
2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester 1 (1 g,
5.43 mmol) in DCM (60 mL) is added MCPBA (2.81 g, 16.29 mmol)
portion wise at rt. The resulting solution is stirred at rt
overnight. A solution of Na.sub.2S.sub.2O.sub.3 (1.6 g) in water
(60 mL) is added. The mixture is stirred at rt for 20 min. The
layer is separated, and the water layer is extracted with DCM
(2.times.20 mL). The combined DCM layer is washed with saturated
NaHCO.sub.3 (3.times.20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford
2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester as a
solid (1.05 g, 90%). MS: 217 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 3.41 (s, 3H), 4.06 (s, 3H), 9.44 (s, 2H).
[0701] Step 2: To a solution of
2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester 2 (2.5
g, 11.56 mmol) in DCM (30 mL) is added a solution of
tetrabutylammonium cyanide (3.1 g, 11.56 mmol) in water (30 mL)
slowly at rt. The mixture is stirred for 80 min. The mixture is
washed with water (2.times.20 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
column chromatography eluting with 5-60% EtOAc in heptane to afford
2-cyano-pyrimidine-5-carboxylic acid methyl ester (1.16 g, 61%) as
a solid. MS: 164 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
4.05 (s, 3H), 9.37 (s, 2H).
[0702] Step 3: To a solution of 2-cyano-pyrimidine-5-carboxylic
acid methyl ester 3 (1 g, 6.13 mmol) in MeOH (20 mL) at rt is added
hydroxylamine hydrochloride (0.64 g, 9.2 mmol) and sodium acetate
(0.76 g, 9.2 mmol). The resulting mixture is heated to reflux for 2
hours. The mixture is cooled to rt and concentrated in vacuo. Water
(30 mL) is added to the residue, and the solid is filtered, and
washed with water twice. The solid is dried in vacuum oven
overnight to afford
2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl
ester (1.09 g, 91%) as a solid. MS: 197 (M+H).
[0703] Step 4: To a solution of
2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl
ester (900 mg, 4.59 mmol) in pyridine (15 mL) is added acetyl
chloride (432 mg, 5.5 mmol) dropwise. The resulting solution is
stirred at rt for 1 hour, and heated to reflux for 3 h. The
solution is cooled to rt and concentrated in vacuo. Water (30 mL)
is added to the residue, and the mixture is extracted with EtOAc
(3.times.20 mL). The combined organic layer is washed with
saturated NaHCO.sub.3, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford
2-(5-methyl-[1,2,3]oxadiazo-3-yl)-pyrimidine-5-carboxylic acid
methyl ester (900 mg, 89%) as a solid. MS: 221 (M+H).
[0704] Step 5: To a solution of
2-(5-methyl-[1,2,3]oxadiazo-3-yl)-pyrimidine-5-carboxylic acid
methyl ester (900 mg) in MeOH (20 mL) is added a solution of LiOH
(100 mg) in water (20 mL) at 0.degree. C. The ice-bath is removed,
and the mixture is stirred for another 10 min. The solvent is
evaporated, and water (20 mL) is added. The water solution is
washed with ether (2.times.20 mL), and acidified with 2 N HCl to pH
3. The resulting precipitate is filtered, washed with water and
dried in vacuum oven overnight to afford 2-(5-methyl-[1,
2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (350 mg, 37%) as a
solid. MS: 207 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
2.73 (s, 3H), 9.39 (s, 2H).
[0705] Step 6: Following procedures similar to those of Example 44,
but substituting
2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid for
2-phenyl-pyriminde-5-carboxylic acid, and substituting
2-(4-amino-piperazin-1-yl)-ethanol for 1-aminopiperidine, there is
prepared 2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic
acid [4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide as a solid. MS: 334
(M+H). IC.sub.50=461 nM.
Example 49
2-(5-Methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide
##STR00055##
[0707] Following procedures similar to those of Example 44, but
substituting
2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid for
2-phenyl-pyriminde-5-carboxylic acid, and substituting
morpholine-4-ylamine for 1-aminopiperidine, there is prepared
2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide as a solid. MS: 291 (M+H).
Example 50
2-Benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide
##STR00056##
[0709] Step 1: 5-Bromo-2-chloropyrimidine (7.51 g, 38.83 mmol) is
dissolved in DMSO (20 mL) is added to a mixture of NaCN (1.9 g,
38.83 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.87 g, 7.77 mmol)
in DMSO (10 mL) and water (20 mL). The mixture is stirred at rt
overnight, and then water (100 mL) is added. The mixture is
extracted with ether (3.times.100 mL). The combined organic layer
is dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
afford 5-bromo-pyrimidine-2-carbonitrile (6.28 g, 88%) as a solid.
MS: 184 (M+H).
[0710] Step 2: 5-Bromo-pyrimidine-2-carbonitrile (2.5 g, 13.59
mmol) is dissolved ether (30 mL), and PhMgBr (3 ether solution,
13.59 mmol, 4.53 mL) is added dropwise at rt. The mixture is heated
to reflux for 3 h under N.sub.2, and then cooled to rt. THF (30 mL)
is added followed by the addition of 2 N aqueous HCl (10 mL). The
resulting solution is stirred at rt for 30 min, and water (30 mL)
is added. The aqueous layer is extracted with EtOAc (3.times.20
mL). The combined organic layer is washed with saturated aqueous
NaHCO.sub.3 (15 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting 70% EtOAc in heptane to afford
(5-bromo-pyrimidine-2-yl)-phenyl-methanone (3.01 g, 84%) as a
solid. MS: 264 (M+H).
[0711] Step 3: (5-Bromo-pyrimidine-2-yl)-phenyl-methanone (1.6 g,
6.08 mmol) is dissolved in dimethylacetamide (20 mL), and potassium
hexacyanoferrate(II) trihydrate (0.57 g, 1.34 mmol) is added,
followed by Na.sub.2CO.sub.3 (0.64 g, 6.08 mmol), and palladium
(II) acetate (68 mg, 0.3 mmol). The mixture is heated to
150.degree. C. under N.sub.2 for 3 h, and then cooled to rt. EtOAc
(30 mL) is added and the mixture is filtered. The filtrate is
washed with water (2.times.15 mL) and 5% aqueous NH.sub.4OH (15
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The residue is purified by silica gel chromatography eluting with
70% EtOAc in heptane to afford 2-benzoyl-pyrimidine-5-carbonitrile
(0.53 g, 42%) as a solid. MS: 210 (M+H).
[0712] Step 4: 2-Benzoyl-pyrimidine-5-carbonitrile (500 mg, 2.39
mmol) is suspended in MeOH (5 mL), a solution of KOH (148 mg, 2.63
mmol) in water (5 mL) is added in one portion at 0.degree. C. The
mixture is stirred at 0.degree. C. for 25 min, and then acidified
with 2 N aqueous HCl to pH 3. MeOH is evaporated in vacuo and the
residue is extracted with DCM (2.times.5 mL). The combined organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo to afford 2-benzoyl-pyrimidine-5-carboxylic acid methyl ester
(500 mg, 86%) as an oil. MS: 243 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 4.05 (s, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 8.01
(m, 2H), 9.46 (s, 2H).
[0713] Step 5: 2-Benzoyl-pyrimidine-5-carboxylic acid methyl ester
(420 mg, 1.73 mmol) is dissolved in THF (5 mL), and a solution of
LiOH (46 mg, 1.91 mmol) in water (5 mL) is added in one portion at
0.degree. C. The mixture is stirred at 0.degree. C. for 60 min. THF
is evaporated in vacuo, and the residue is diluted with water (5
mL) and washed with ether (10 mL). The aqueous layer is acidified
with 2 N aqueous HCl to pH 3. The resulting precipitate is
collected by filtration, washed with water three times, and dried
in vacuum oven overnight to afford
2-benzoyl-pyrimidine-5-carboxylic acid (260 mg, 66%). MS: 229
(M+H); .sup.1H NMR (300 MHz, DMSO): .delta. 7.60 (m, 3H), 7.73 (m,
1H), 7.85 (m, 2H), 9.4 (s, 1H).
[0714] Step 6: 2-Benzoyl-pyrimidine-5-carboxylic acid (50 mg, 0.22
mmol) is dissolved in anhydrous DCM (5 mL), and a 2 M oxalyl
chloride (0.26 mmol, 0.13 mL) solution in DCM is added at rt
followed by one drop of DMF. The mixture is stirred at rt for 2 h,
and then concentrated in vacuo. The residue is dissolved in DCM (5
mL), and morpholine-4-ylamine (0.24 mmol, 25 mg) is added, followed
by DIPEA (0.44 mmol, 57 mg). The reaction mixture is stirred at rt
overnight, and then concentrated in vacuo. The residue is purified
by silica gel column chromatography eluting with 10% MeOH in DCM to
afford 2-benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide
(42 mg) as a solid. MS: 313 (M+H). IC.sub.50=342 nM.
Example 51
2-Benzoyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide
##STR00057##
[0716] Following procedures similar to those of Example 49, step 6,
but substituting 2-(4-amino-piperazin-1-yl)-ethanol for
morpholine-4-ylamine, there is prepared
2-benzoyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide as a solid. MS: 356
(M+H). IC.sub.50=665 nM.
Example 52
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[5-trifluoromethyl-pyridin-2-yl]-hydrazide
##STR00058##
[0718] To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (100
mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol),
1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, 0.57 mmol)
and DIPEA (0.57 mmol) in DCM (5 mL) is added
N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine (109 mg, 0.57
mmol). The reaction mixture is stirred at rt for 18 hours and then
concentrated. The residue is purified by silica gel chromatography
eluting with 10-75% EtOAc in heptane to afford
2-phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[5-trifluoromethyl-pyridin-2-yl]-hydrazide as a solid
(189 mg). MS: 374 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
3.54 (s, 3H), 6.82 (d, 1H), 7.53-7.59 (m, 3H), 7.74 (d, 1H), 8.45
(d, 2H), 8.53 (d, 2H), 9.25 (s, 2H). IC.sub.50=100 nM.
Example 53
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[4-trifluoromethyl-pyridin-2-yl]-hydrazide
##STR00059##
[0720] Following procedures similar to those of Example 52, but
substituting N-methyl-N-(4-trifluoromethyl-pyridin-2-yl)-hydrazine
(109 mg, 0.57 mmol) for
N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine, there is
prepared 2-phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-[4-trifluoromethyl-pyridin-2-yl]-hydrazide as a solid.
MS: 374 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.54 (s,
3H), 6.95 (m, 2H), 7.50-7.68 (m, 3H), 8.35 (d, 1H), 8.4 (s, 1H),
8.52 (d, 2H), 9.26 (s, 2H).
Example 54
2-Phenyl-pyrimidine-5-carboxylic acid N'-pyridin-2-yl-hydrazide
##STR00060##
[0722] Following procedures similar to those of Example 52, but
substituting 2-hydrazinopyridine (54 mg, 0.52 mmol) for
N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine, there is
prepared 2-phenyl-pyrimidine-5-carboxylic acid
N'-pyridin-2-yl-hydrazide as a solid (56 mg). MS: 292 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 6.72-6.8 (m, 2H),
7.53-7.62 (m, 4H), 8.09 (m, 2H), 8.48 (d, 2H), 8.62 (s, 1H), 9.34
(s, 2H).
Example 55
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-chloro-phenyl)-hydrazide
##STR00061##
[0724] Following procedures similar to those of Example 52, but
substituting 2-chlorophenylhydrazine hydrochloride (93 mg, 0.52
mmol) for N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine,
and using 1.14 mmol of DIPEA, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
N'-(2-chloro-phenyl)-hydrazide as a solid (65 mg). MS: 325 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.65-6.75 (m, 2H),
6.90-7.05 (m, 2H), 7.25 (t, 1H), 7.39 (d, 1H), 7.58 (m, 3H), 8 (s,
1H), 8.55 (d, 2H), 9.25 (s, 2H).
Example 56
2-Phenyl-pyrimidine-5-carboxylic acid
N'-(2-oxo-piperidin-1-yl)-amide
##STR00062##
[0726] Step 1: A mixture of Methyl-5-bromovalerate (3 g, 15.4 mmol)
and hydrazine hydrate (55%, 15.4 mmol) in MeOH (50 mL) is stirred
at rt for 18 h. A solution of NaOMe (15.4 mmol) in MeOH (10 mL) is
added and the reaction mixture is stirred at rt for 18 h. The
reaction mixture is concentrated in vacuo. The residue is
triturated with cold MeOH and then filtered. The filtrate is
concentrated in vacuo. The residue is placed on a SCX column (10 g)
and the column is washed with MeOH (3.times.20 mL. The product is
eluted with 7 M ammonia in MeOH to afford 1-amino-piperidin-2-one
as an oil. MS: 137 (M+Na).
[0727] Step 2: To a solution of 2-phenyl-pyrimidine-5-carboxylic
acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, 0.57
mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, 0.57
mmol) and DIPEA (0.57 mmol) in DCM (5 mL) is added
1-amino-piperidin-2-one (64 mg, 0.57 mmol), and the mixture is
stirred at rt for 18 h. DCM (15 mL) is added and the mixture is
washed with 0.5 N aqueous HCl (25 mL) and brine, and dried
(Na.sub.2SO.sub.4.), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography through eluting
with 50-100% EtOAc in heptane to afford
2-phenyl-pyrimidine-5-carboxylic acid
N'-(2-oxo-piperidin-1-yl)-amide (20 mg) as a solid. MS: 297 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.96-2.10 (m, 4H), 2.60
(t, 2H), 3.77 (t, 2H), 7.51-7.56 (m, 3H), 8.51 (d, 2H), 9.02 (bs,
1H), 9.16 (s, 2H). IC.sub.50=55 nM.
Example 57
2-Phenyl-pyrimidine-5-carboxylic acid
N'-cyclohexyl-N'-methyl-hydrazide
##STR00063##
[0729] Following procedures similar to those of Example 52, but
substituting N-methyl-N-cyclohexyl-hydrazine hydrochloride (72 mg,
0.44 mmol) for
N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine, and using
0.88 mmol of DIPEA, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
N'-cyclohexyl-N'-methyl-hydrazide as a solid (40 mg). MS: 311
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 0.9-1.35 (m,
5H), 1.60-1.95 (m, 6H), 3.25 (s, 3H) 7.53-7.62 (m, 3H), 8.09 (m,
2H), 9.09 (s, 2H). IC.sub.50=146.5 nM.
Example 58
2-Phenyoxy-pyrimidine-5-carboxylic acid N'-morpholin-4-yl-amide
##STR00064##
[0731] Step 1: To a solution of
2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester (1 g,
5.43 mmol) in DCM (60 mL) is added MCPBA (2.81 g, 16.29 mmol)
portion wise at rt. The resulting solution is stirred at rt
overnight. A solution of Na.sub.2S.sub.2O.sub.3 (1.6 g) in water
(60 mL) is added. The mixture is stirred at rt for 20 min. The
organic layer and aqueous layer are separated, and the aqueous
layer is extracted with DCM (2.times.20 mL). The combined organic
layer is washed with saturated aqueous NaHCO.sub.3 (3.times.20 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
afford 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester
(1.05 g, 90%) as a solid. MS: 217 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 3.41 (s, 3H), 4.06 (s, 3H), 9.44 (s, 2H).
[0732] Step 2: To a solution of
2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester (0.8 g,
3.7 mmol) in NMP (3 mL) is added sodium phenoxide trihydrate (0.68
g, 4 mmol). The mixture is heated at 100.degree. C. in Biotage
Microwave for 60 sec. The reaction is poured into water and the
precipitate is collated by filtration and dried to afford
2-phenoxy-pyrimidine-5-carboxylic acid methyl ester (0.56 g, 66%)
as a solid. MS: 231 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 4.75 (s, 3H), 7.19-7.33 (m, 3H), 7.46 (t, 2H) 9.10 (s,
2H).
[0733] Step 3: To a solution of 2-phenoxy-pyrimidine-5-carboxylic
acid methyl ester (0.5 g, 2.17 mmol) in THF (10 mL) and water (5
mL) is added LiOH (105 mg, 4.35 mmol). The reaction is stirred at
0.degree. C. for 1 h. The THF is evaporated and the aqueous reissue
is washed with ether, acidified with 2 M aqueous HCl. The resulting
precipitate is filtered and dried to afford
2-phenoxy-pyrimidine-5-carboxylic acid (0.34 g, 73%) as a solid.
MS: 217 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.20-7.35
(m, 3H), 7.47 (t, 2H) 9.16 (s, 2H).
[0734] Step 4: To a solution of 2-phenoxy-pyrimidine-5-carboxylic
acid (60 mg, 0.28 mmol) in DCM (5 mL) is added oxalyl chloride (2M
in DCM, 0.15 mL, 0.29 mmol) and 1 drop of DMF. The reaction is
stirred at rt for 1 h and concentrated in vacuo. The residue is
dissolved in DCM (3 mL), and DIPEA (53 .mu.L, 0.3 mmol) and
4-amino-morpholine (30 .mu.L, 0.3 mmol) is added. The reaction is
stirred at rt for 18 h and then water and DCM are added. The
organic layer is separated, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 20-100% EtOAc in heptane to afford
2-phenyloxy-pyrimidine-5-carboxylic acid N'-morpholin-4-yl-amide
(20 mg) as a solid. MS: 301 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 2.85-3.05 (m, 4H), 3.75-3.95 (m, 4H),
7.18-7.35 (m, 3H), 7.45 (t, 2H), 8.95 (s, 2H). IC.sub.50=227
nM.
Example 59
2-(3-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00065##
[0736] Step 1: 2-Methylsulfanyl-pyrimidine-5-carboxylicacid methyl
ester (323 mg, 1.75 mmol), Copper(I) thiophene-2-carboxylate (501
mg, 2.63 mmol), tetrakis(triphenylphosphine) palladium(0) (202 mg,
0.175 mmol) and 3-methoxyphenylboronic acid (400 mg, 2.63 mmol) are
taken in a glass tube, evacuated, refilled with N.sub.2, added
anhydrous THF (6 mL) and is heated overnight at 85.degree. C. after
closing with a cap. The reaction is cooled to rt, diluted with
EtOAc and ammonium hydroxide is added. The organic layer is
seperated, dried (MgSO.sub.4), filtered and concentrated in vacuo.
The residue is purified by flash silica gel chromatography to
afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl
ester (152 mg) as a powder. MS: 245 (M+H); .sup.1H NMR
(CDCl.sub.3): .delta. 4.00 (s, 3H), 4.82 (d, 2H), 7.55 (m, 2H),
8.46 (m, 1H), 8.53 (s, 1H), 9.33 (s, 2H).
[0737] Step 2: A mixture of
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester (145
mg, 0.59 mmol), lithium hydroxide monohydrate (49.5 mg, 1.18 mmol),
MeOH (1.5 mL), water (1.5 mL) and THF (1.5 ml) is stirred at rt for
3.5 hrs. The reaction mixture is concentrated, and water (1 mL) and
1 N aqueous HCl (1.2 mL) are added. The precipitated product is
filtered and dried to afford
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (140 mg). MS: 231
(M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 4.62 (s, 3H), 7.54 (m,
2H), 8.14 (s, 1H), 8.34 (m, 1H), 8.46 (s, 1H), 9.30 (s, 2H).
[0738] Step 3: A mixture of
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (135 mg, 0.58
mmol), 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (76 mg,
0.58 mmol), DMTMM (171 mg, 0.6 mmol) and DMF (3 mL) is stirred at
rt for 2 days. Water (3 ml) is added, and the precipitated product
is filtered, washed with water and dried to afford
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (127 mg).
MS: 341 (M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.91 (s, 3H),
4.23 (s, 3H), 4.62 (s, 2H), 7.53 (m, 2H), 8.34 (m, 1H), 8.46 (s,
1H), 9.27 (s, 2H), 9.97 (s, 1H), 11.08 (s, 1H). IC.sub.50=174.5
nM.
Example 60
2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide
##STR00066##
[0740] Step 1: To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-one
(5.509 g, 55.0 mmol) in MeOH (40 mL) is added 25 wt % NaOMe
solution in methanol (12.7 mL, 58.8 mmol). The mixture is stirred
at rt for 15 min and then concentrated in vacuo. The residue is
added to a solution of tetrabutylammonium bromide (0.358 g, 1.08
mmol) and chloro-acetone (4.6 ml, 54.9 mmol) in CHCl.sub.3 (33 mL),
and the mixture is heated to reflux for 5 h under N.sub.2. The
mixture is cooled to rt and stirred overnight. The resulting slurry
is filtered, and the filtrate is concentrated in vacuo. The residue
is purified on a pad of silica gel, eluting with
2:1:1/heptane:EtOAc:DCM to afford
5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (7.32 g, 86%) as
a crystalline solid. MS: 157 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 4.46 (s, 2H), 2.27 (s, 3H), 2.21 (s, 3H).
[0741] Step 2: To a solution of
5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (1.518 g, 9.72
mmol) in a mixture of 2-propanol (8.8 mL) and water (0.22 mL) is
added methyl hydrazine (0.79 mL, 14.6 mmol). The reaction mixture
is heated to reflux under N.sub.2 for 4 h, and then a solution of
oxalic acid (0.273 g, 2.92 mmol) in 2-propanol (4 mL) is added. The
resulting precipitate is removed by filtration. The filtrate is
concentrated in vacuo and the residue dissolved in 2-propanol (25
mL). The solution is chilled and Et.sub.2O is added. The
precipitate is collected by filtration and dried to afford
N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide
(0.96 g, 54%) as a crystalline solid. MS: 185 (M+H); .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.28 (s, 1H), 4.18 (s, 2H), 3.28
(s, 3H), 2.02 (s, 3H), 1.95 (s, 2H).
[0742] Step 3: To a slurry of
N-(2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide
(0.34 g, 1.846 mmol) in MeOH (3 mL) is added concentrated HCl (0.25
mL, 2.9 mmol). The mixture is heated to reflux for 3 h. The mixture
is then chilled to 0.degree. C., adjusted to pH 12 with 1 M aqueous
NaOH (2.9 mL) and concentrated in vacuo. CH.sub.3CN is added to the
residue with stirring and the mixture is filtered. The filtrate is
concentrated in vacuo. CH.sub.3CN is added to the residue with
stirring and the mixture is filtered. The filtrate is concentrated
in vacuo to afford
4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (100%)).
MS: 143 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.6-3.6
(broad peak, 2H), 4.02 (s, 2H), 3.29 (s, 3H), 1.95 (s, 3H).
[0743] Step 4: To a solution of
4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.219 g,
1.58 mmol) and 2-phenyl-pyrimidine-5-carboxylic acid (0.317 g, 1.58
mmol) in dry DMF (10 mL) under N.sub.2 is added DMTMM (0.46 g, 1.66
mmol). The mixture is stirred at rt for 22 h, then diluted with
EtOAc (70 mL), and washed successively with saturated aqueous
NaHCO.sub.3 solution (2.times.10 mL) and brine (10 mL). The organic
phase is dried (MgSO.sub.4), filtered and concentrated in vacuo.
The residue is purified by silica gel chromatography eluting with
heptane:EtOAc gradient to afford 2-phenyl-pyrimidine-5-carboxylic
acid (2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-amide
as a solid (0.28 g, 55%). MS: 325 (M+H); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.24 (s, 2H), 8.45 (dd, J=7.7, 2.0 Hz, 2H),
7.52-7.62 (m, 3H), 4.25 (s, 2H), 3.18 (s, 3H), 1.95 (s, 3H).
Example 61
2-Phenyl-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide
##STR00067##
[0745] Step 1: To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-one
(1.01 g, 10.09 mmol) in MeOH (8 mL) is added 25 wt % NaOMe solution
in methanol (2.32 mL, 10.8 mmol). The mixture is stirred at rt for
15 min and then concentrated in vacuo. The residue is added to a
solution of tetrabutylammonium bromide (0.07 g, 0.22 mmol) and
1-chloropinacolone (1.35 mL, 10.07 mmol). in CHCl.sub.3 (7 mL), and
the mixture is heated to reflux for 5 h under N.sub.2. The mixture
is cooled to rt and stirred over the weekend at rt. The resulting
slurry is filtered, and the filtrate is concentrated in vacuo to
afford 3-(3,3-dimethyl-2-oxo-butyl)-3H-1,314-oxadiazol-2-one (1.876
g, 94%) as an oil. MS: 199 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 4.62 (s, 2H), 2.26 (s, 3H), 1.23 (s, 9H).
[0746] Step 2: To a solution of
3-(3,3-dimethyl-2-oxo-butyl)-3H-1,3,4-oxadiazol-2-one (0.91 g, 4.59
mmol) in a mixture of 2-propanol (4 mL) and water (0.11 mL) is
added hydrazine monohydrate (0.34 mL, 6.89 mmol). The reaction
mixture is heated to reflux under nitrogen for 5 h, then a solution
of oxalic acid (0.13 g, 1.38 mmol) in 2-propanol (5 mL) is added to
the hot solution. The resulting precipitate is removed hot by
filtration. The filtrate is concentrated in vacuo and the residue
is purified on a pad of silica gel, eluting with heptane:EtOAc
gradient to afford
N-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide
(0.546 g, 56%) as a solid. MS: 213 (M+H); .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.29 (s, 1H), 7.64 (s, 1H), 4.22 (s, 2H),
2.04 (s, 3H), 1.15 (s, 9H).
[0747] Step 3: To a slurry of
N-(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide
(0.51 g, 2.40 mmol) in MeOH (5 mL) is added concentrated HCl (0.33
mL, 3.84 mmol). The mixture is heated to reflux for 3 h. The
mixture is then chilled to 0.degree. C. and basified with 1 M
aqueous NaOH (2.9 mL) to pH 12, and concentrated in vacuo. EtOH is
added to the residue with stirring and the mixture is filtered. The
filtrate is concentrated in vacuo. CH.sub.3CN is added to the
residue with stirring and the mixture is filtered. The filtrate is
concentrated in vacuo to afford
4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.354 g,
84%) as a solid. MS: 171 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.49 (br s, 1H), 4.22 (br s, 2H), 4.06 (s, 2H), 1.15 (s,
9H).
[0748] Step 4: Following the procedure similar to those of Example
60, step 4, but substituting
4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazin-3-one for
4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one, there is
prepared 2-phenyl-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-amide (74%)
as a solid. MS: 353 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.09 (s, 1H), 10.03 (s, 1H), 9.27 (s, 2H), 8.45 (dd,
J=7.7, 2.0 Hz, 2H), 7.52-7.60 (m, 3H), 4.29 (s, 2H), 1.13 (s,
9H).
Example 62
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide
##STR00068##
[0750] Step 1: To a solution of
5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (2.052 g, 13.14
mmol) in a mixture of 2-propanol (12 mL) and water (0.3 mL) is
added hydrazine monohydrate (0.96 mL, 19.8 mmol). The mixture is
stirred at rt under N.sub.2 for 15 h, and then heated to reflux for
7 h. A solution of oxalic acid (0.363 g, 4.032 mmol) in 2-propanol
(6 mL) is added to the warm reaction solution. The resulting
precipitate is removed by filtration through a coarse porosity
sintered glass funnel, and the filtrate is concentrated in vacuo to
approximately 10 mL in total volume. The concentrated solution is
chilled to -12.degree. C., and the resulting crystals are collected
by filtration and dried to afford
N-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide
(1.562 g, 70%). MS: 171 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.10 (br s, 1H), 7.57 (br s, 1H), 4.20 (s, 2H), 2.04 (s,
3H), 1.95 (s, 3H); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.98
(s, 1), 9.74 (s, 1), 4.04 (s, 2), 1.84 (s, 6).
[0751] Step 2: Following the procedure similar to those of Example
35, step 4, but substituting
N-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide for
N-[6-(4-fluoro-phenyl)-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl]-acetamide-
, there is prepared
4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazin-3-one (92%) as a
solid. MS: 129 (M+H); .sup.1H NMR (300 MHz, CD.sub.3CN) .delta.
8.25 (br s, 1H), 4.26 (br s, 2H), 3.96 (s, 2H), 1.85 (s, 3H).
[0752] Step 3: To a solution of
2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.152 g, 0.75 mmol),
in dry DCM (3 mL) and DMF (0.9 .mu.L) in a dry flask under N.sub.2
is added oxalyl chloride (74 .mu.L, 0.86 mmol). The reaction
mixture is stirred at rt for 1 h. The solvent is evaporated and
toluene is added and evaporated three times. The residue is
dissolved in dry DCM (3 mL), and a solution of
4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.77 g, 0.6
mmol) in DCM (5 mL) is added followed by the addition of DIPEA
(0.14 mL, 0.79 mmol). The mixture is stirred at rt overnight, and
then concentrated in vacuo. The residue is diluted with water and
adjusted to pH 8.5 with saturated aqueous NaHCO.sub.3 solution. The
resulting precipitate is filtered to afford
2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)amide (0.043 g,
23%). MS: 312 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.11 (s, 1H), 9.95 (s, 1H), 9.31 (s, 2H), 8.78 (d, 1H), 8.45 (d,
1H), 8.01 (tr, 1H), 7.58 (dd, 1H), 4.22 (2, 2H), 1.91 (s, 3H).
Example 63
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide
##STR00069##
[0754] Following the procedure similar to those of Example 62, step
3, but substituting 2-(3-Fluoro-phenyl)-pyrimidine-5-carbonyl
chloride for 2-pyridin-2-yl-pyrimidine-5-carbonyl chloride,
substituting
4-amino-6-tert-butyl-4,5-dihydro-2H-1,2,4-triazin-3-one for
4-amino-6-methyl-4,5-dihydro-2H-1,2,4-triazin-3-one, and
substituting Et.sub.3N for DIPEA, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-tert-butyl-3-oxo-2,5-dihydro-3H-1,2,4-triazine-4-yl)-amide
(0.067 g, 61%). MS: 371 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 9.26 (s, 2H), 8.35 (d, J=8.1 Hz, 1H), 8.21 (d, J=10.3 Hz),
7.55 (q, J=10.3 Hz, 1H), 7.30 (tr, J=8.2 Hz, 1H), 4.37 (s, 2H),
1.19 (s, 9H).
Example 64
3-{2,4-Dioxo-3-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-
-pyrimidin-5-yl}-propionic acid methyl ester
##STR00070##
[0756] A mixture of 2-phenyl-pyrimidine-5-carboxylic acid (1.17
mmol), 1-hydroxybenzotriazole (1.99 mmol), and PS-DCC (1.21 mmol/g,
2.34 mmol in DMF (8 mL) is shaken at rt for 60 min.
3-{3-Amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester (1.17 mmol) is added and the mixture is shaken at rt
for 2-4 days. Polymer supported-trisamine (PS-trisamine) (4.08
mmol/g, 3.51 mmol) is added and the mixture is continually shaken
at rt for 18 hours. The solid is filtered and washed with MeOH. The
filtrate is concentrated. The residue is purified by silica gel
chromatography eluting with 10-60% EtOAc in hexanes to afford
3-{2,4-dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-
-pyrimidin-5-yl-propionic acid methyl ester (115 mg, 25%) as a
solid. MS: 397 (M+H) 397; .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 2.57-2.76 (m, 2H), 2.80-3.00 (m, 2H), 3.64 (s, 3H), 5.30
(br. N--H), 7.37-7.55 (m, 3H), 8.35 (d, 2H), 9.26 (s, 2H).
Example 65
3-{2,4-Dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro--
pyrimidin-5-yl}-propionic acid
##STR00071##
[0758]
3-{2,4-Dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetr-
ahydro-pyrimidin-5-yl}-propionic acid methyl ester (0.22 mol) is
hydrolyzed by LiOH (0.88 mol) in MeOH/water/THF (1:1:1) at rt
overnight. MeOH and THF are evaporated in vacuo. The residue is
acidified by 5% aqueous HCl. The resulting precipitate is collected
and dried to afford
3-{2,4-dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-
-pyrimidin-5-yl}-propionic acid (40 mg, 48%). MS: 383 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.68-2.77 (m, 2H),
2.98-2.90 (m, 2H), 5.49 (s. N--H), 7.48-7.60 (m, 3H), 8.41-8.56 (m,
2H), 9.32 (s, 2H).
Example 66
2-Phenyl-pyrimidine-5-carboxylic acid
(4-methyl-piperazin-1-yl)-amide
##STR00072##
[0760] Following procedures similar to those of Example 64 but
substituting 4-methyl-piperazin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (4-methyl-piperazin-1-yl)-amide.
Example 67
2-Phenyl-pyrimidine-5-carboxylic acid
(4-methyl-piperazin-1-yl)-amide dihydrochloride
##STR00073##
[0762] 2-Phenyl-pyrimidine-5-carboxylic acid
(4-methyl-piperazin-1-yl)-amide is dissolved in HCl methanol
solution and evaporated methanol to dryness to afford
2-phenyl-pyrimidine-5-carboxylic acid
(4-methyl-piperazin-1-yl)-amide dihydrochloride as a solid. MS: 298
(M+H).
Example 68
2-Phenyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide
##STR00074##
[0764] Following procedures similar to those of Example 64 but
substituting 4-aminomorpholine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid morpholin-4-ylamide (71%) as a solid. MS: 285 (M+H); .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 2.90-3.00 (m, 2H), 3.80-3.85 (m,
2H), 7.44-7.58 (m, 3H), 8.45-8.53 (m, 2H), 9.18 (s, 2H).
Example 69
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide
##STR00075##
[0766] Following procedures similar to those of Example 64 but
substituting 2-(4-amino-piperazin-1-yl)-ethanol for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-phenyl-pyrimidine-5-carboxylic[4-(2-hydroxy-ethyl)-piperazin-1-y]-amide
(25%) as a solid. MS: 328 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 2.65 (t, 2H), 2.80 (br, 2H), 3.04 (br, 2H), 3.73 (t, 2H),
7.24-7.34 (m, H), 7.47-7.57 (m, 3H), 7.62-7.73 (m, H), 8.43-8.52
(m, 2H), 9.18 (s, 2H).
Example 70
2-Phenyl-pyrimidine-5-carboxylic acid
((s)-2-methoxymethyl)-pyrrolidin-1-yl]-amide
##STR00076##
[0768] Following procedures similar to those of Example 64 but
substituting (S)-2-methoxymethyl-pyrrolidin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid ((s)-2-methoxymethyl) -pyrrolidin-1-yl]-amide (63%) as a
solid. MS: 313 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
1.57-2.15 (m, 4H), 2.70-3.70 (m, 8H), 6.93 (br, 0.4N--H), 7.81 (br,
0.6N--H), 7.50 (m, 3H), 8.48 (m, 2H), 9.10-9.38 (d, 2H).
Example 71
2-Phenyl-pyrimidine-5-carboxylic acid
((R)-2-methoxymethyl)-pyrrolidin-1-yl]-amide
##STR00077##
[0770] Following procedures similar to those of Example 64 but
substituting (R)-2-methoxymethyl-pyrrolidin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid ((R)-2-methoxymethyl)-pyrrolidin-1-yl]-amide (66%) as a solid.
MS: 313 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.57-2.15
(m, 4H), 2.71-3.63 (m, 8H), 6.93 (br, 0.4N--H), 7.71 (br, 0.6N--H),
7.50 (m, 3H), 8.50 (m, 2H), 9.10-9.38 (d, 2H).
Example 72
2-Phenyl-pyrimidine-5-carboxylic acid
(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-amide
##STR00078##
[0772] Following procedures similar to those of Example 64 but
substituting 5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylamine
for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic
acid methyl ester, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
(5-bromo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-amide (34%) as a
solid. MS: 389 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.49-7.62 (m, 3H), 7.98 (br, 3H), 8.23 (s, H), 8.54 (d, 2H), 9.29
(s, 2H). IC.sub.50=107.5 nM.
Example 73
2-Phenyl-pyrimidine-5-carboxylic acid
(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-amide
##STR00079##
[0774] Following procedures similar to those of Example 64 but
substituting 3-isopropyl-5-oxo-1,5-dihydro(1,2,4)-triazol-4-ylamine
for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic
acid methyl ester, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
(3-isopropyl-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-amide (25%) as
a solid. MS: 325 (M+H).
Example 74
2-Phenyl-pyrimidine-5-carboxylic acid pyarrol-1-ylamide
##STR00080##
[0776] Following procedures similar to those of Example 64 but
substituting pyrrol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid pyrrol-1-ylamide (62%) as a solid. MS: 265 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 6.25 (d, 2H), 6.76 (d, 2H),
7.48-7.63 (m, 3H), 8.52 (d, 2H), 8.95-9.60 (br, 2H).
Example 75
2-Phenyl-pyrimidine-5-carboxylic acid
(5-morpholin-4-ylmethyl-2-oxo-oxazolidin-3-yl)-amide
##STR00081##
[0778] Following procedures similar to those of Example 64 but
substituting 5-morpholin-4-ylmethyl-2-oxo-oxazolidin-3-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (5-morpholin-4-ylmethyl-2-oxo-oxazolidin-3-yl)-amide (51%) as
a solid. MS: 384 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
2.50-2.95 (m, 6H), 3.64-3.85 (m, 5H), 3.98 (t, H), 4.88 (m, H),
7.48-7.60 (m, 3H), 8.49 (d, 2H), 9.16 (s, 2H), 9.37 (br. N--H).
IC.sub.50=20 nM.
Example 76
2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl]-amide
##STR00082##
[0780] Following procedures similar to those of Example 64 but
substituting 4-cyclopentyl-piperazin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (4-cyclopentyl-piperazin-1-yl]-amide (67%) as a solid. MS: 352
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.25-2.00 (m,
8H), 2.00-3.35 (m, 9H), 6.70-7.40 (m, N--H), 7.40-7.60 (m, 3H),
8.50 (s, 2H), 8.86-9.38 (m, 2H).
Example 77
2-Phenyl-pyrimidine-5-carboxylic acid
(2-oxo-oxazolidin-3-yl)-amide
##STR00083##
[0782] Following procedures similar to those of Example 64 but
substituting 2-oxo-oxazolidin-3-ylamine hydrochloride for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (2-oxo-oxazolidin-3-yl)-amide (18%) as a solid. MS: 285 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.94 (t, 2H), 4.55 (t,
2H), 7.46-7.62 (m, 3H), 8.53 (d, 2H), 9.30 (d, 2H). IC.sub.50=49
nM.
Example 78
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl]-amide
##STR00084##
[0784] Following procedures similar to those of Example 64 but
substituting 6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-ylamine
for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic
acid methyl ester, there is prepared
4-methyl-2-phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl]-amide (87%) as
a solid. MS: 325 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
1.95 (s, 3H), 3.72 (s, 3H), 4.30 (s, 2H), 7.34-7.58 (m, 4H), 7.72
(br, H), 8.92 (br, H), 8.43 (d, 2H), 8.87 (s, H), 9.46 (br, H).
Example 79
[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl
ester
##STR00085##
[0786] Et.sub.3N (13.15 mmol) is added to a stirred solution of
2-phenyl-pyrimidine-5-carboxylic acid chloride (5.26 mmol) and
hydrazine-acetic acid ethyl ester hydrochloride (5 mmol) in DCM (30
mL) at rt, and the mixture is stirred at rt for 5 h. The mixture is
quenched with water and extracted with EtOAc (60 mL). The organic
layer is washed with water (20 mL) and brine (15 mL), dried,
filtered and concentrated in vacuo. The residue is purified by
silical gel chromatography eluting with 5-50% EtOAc in heptane to
afford [N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid
ethyl ester (256 mg, 16%) as a solid. MS: 301 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.35 (s, 3H), 4.20-4.40 (m, 4H),
4.56 (s, 2H), 7.54 (m, 3H), 8.53 (m, 2H), 9.24 (s, 2H).
Example 80
2-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide
##STR00086##
[0788] A mixture of
[N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl
ester (0.37 mmol) in 25% ammonia solution (25 mL) is stirred at rt
over night. The solid is collected by filtration and dried to
afford 2-[N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetamide
(46%). MS: 272 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
4.45 (s, 2H), 7.45-7.56 (m, 3H), 8.40-8.50 (m, 2H), 9.18 (s,
2H).
Example 81
4-[3-(4-Morpholino)propyl]-1-(2-phenyl-pyrimidine-5-carbonyl)-3-thiosemica-
rbazide
##STR00087##
[0790] Following procedures similar to those of Example 64 but
substituting 4-[3-(4-morpholino)-propyl]-3-thiosemicarbazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
4-[3-(4-morpholino)propyl](2-phenyl-pyrimidine-5-carbonyl)-3-thiosemicarb-
azide (32%) as a solid. MS: 401 (M+H); .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 1.67-1.97 (m, 2H), 2.27-2.84 (m, 6H),
3.40-3.86 (m, 6H), 7.34-7.59 (m, 3H), 8.33-8.57 (m, 2H), 9.24 (s,
2H).
Example 82
2-Phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00088##
[0792] Oxalyl chloride in DCM (2 M, 1.5 mL) is added to a solution
of 2-phenyl-pyrimidine-5-carboxylic acid (200 mg, 2 mmol) in DCM
(20 mL) and stirred at rt for 2 h. The reaction solution is
concentrated in vacuo. The residue is dissolved in DCM (20 mL).
N-amino-indoline (268 mg, 2 mmol) and triethylamine (404 mg, 4
mmol) are added and stirred at rt overnight. The mixture is
concentrated in vacuo and the residue is purified by silica gel
column chromatography eluting with 0-40% EtOAc in heptane to afford
2-phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (195 mg, 31%) as a solid. MS: 317
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.07 (t, 2H),
3.77 (t, 2H), 6.76 (m, H), 6.82-6.95 (m, H) 7.09-7.24 (m, 2H),
7.54-7.63 (m, 3H), 8.52 (d, 2H), 9.28 (s, 2H) and
2-phenyl-pyrimidine-5-carboxylic acid (indol-1-yl)-amide (10 mg,
2%). MS: 315 (M+H). IC.sub.50=2 nM.
Example 83
{4-[2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-acetic
acid methyl ester
##STR00089##
[0794] Step 1: Following procedures similar to those of Example 64
but substituting piperazin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid piperazin-1-yl-amide.
[0795] Step 2: Phenyl-pyrimidine-5-carboxylic acid
piperazin-1-yl-amide is dissolved in HCl methanol solution and
evaporated methanol to dryness to afford
2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-yl)-amide
dihydrochloride as a solid.
[0796] Step 3: A suspended solution of
2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide
dihydrochloride (0.5 mmol), methyl bromoacetate (0.5 mmol) and
Na.sub.2CO.sub.3 (2.5 mmol) in wet THF (20 mL) is stirred at rt for
20 h. The mixture is concentrated in vacuo. The residue is purified
by silica gel chromatography eluting with 1-5% methanol in DCM to
afford
{4-[2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-acet- ic
acid methyl ester (135 mg, 76%) as a solid. MS: 356 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 2.60-3.18 (m, 8H), 3.18-3.35 (d,
2H), 3.74 (s, 3H), 6.67 (br, 0.5 N--H) 7.03 (br, 0.5 N--H),
7.46-7.60 (m, 3H), 8.50 (d, 2H), 9.21 (d, 2H).
Example 84
2-Phenyl-pyrimidine-5-carboxylic acid
(4-cyanomethyl-piperazin-1-yl)-amide
##STR00090##
[0798] A solution of 2-phenyl-pyrimidine-5-carboxylic acid
piperazin-1-ylamide dihydrochloride (0.29 mmol), bromoacetonitrile
(0.29 mmol) and Na.sub.2CO.sub.3 (1.46 mmol) in wet THF (8 mL) is
stirred at rt overnight. The reaction mixture is filtered and the
filtrate is concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 1-2% methanol in DCM to
afford 2-phenyl-pyrimidine-5-carboxylic acid
(4-cyanomethyl-piperazin-1-yl)-amide (38 mg, 40%) as a solid. MS:
323 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.60-3.30 (m,
8H), 3.55 (s, 2H), 6.63 (br, 0.5 N--H), 7.14 (br, 0.5 N--H), 7.52
(s, 3H), 8.53 (d, 2H), 9.06-9.38 (m, 2H).
Example 85
Acetic acid
2-{4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl}-ethyl
ester
##STR00091##
[0800] A solution of
2-phenyl-pyrimidine-5-carboxylic[4-(2-hydroxy-ethyl)-piperazin-1-y]-amide
(0.21 mmol), acetyl chloride (1.06 mmol) in pyridine (4 mL) is
stirred at 80.degree. C. overnight. The reaction mixture is
filtered and the filtrate is concentrated in vacuo. The residue is
dissolved in EtOAc (10 mL), washed with water (10 mL), 10%
Na.sub.2CO.sub.3 (10 mL) and brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-5% methanol
in DCM to afford
2-{4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazin-1-yl)-ethyl
ester (12 mg, 15%) as a solid. MS: 370 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 2.08 (s, 3H), 2.42-3.20 (m, 8H), 3.20-3.80 (m,
3H), 4.10-4.52 (m, 2H) 7.42-7.65 (m, 3H), 8.52 (m, 2H), 9.07-9.38
(d, 2H).
Example 86
2-Phenyl-pyrimidine-5-carboxylic acid
(4-acetyl-piperazin-1-yl)-amide
##STR00092##
[0802] A solution of 2-phenyl-pyrimidine-5-carboxylic acid
piperazin-1-ylamide dihydrochloride (0.43 mmol), acetyl chloride
(1.28 mmol) and Et.sub.3N (1.72 mmol) in DMF (8 mL) is stirred at
rt overnight. mixture is concentrated in vacuo. The residue is
dissolved in EtOAc (15 mL), washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is triturated with ether to afford 2-phenyl-pyrimidine-5-carboxylic
acid (4-acetyl-piperazin-1-yl)-amide (98 mg, 71%) as a solid. MS:
326 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.12 (s, 3H),
2.92-3.10 (m, 4H), 3.40-4.10 (m, 4H), 7.43-7.60 (m, 3H), 7.75 (br,
N--H), 8.52 (m, 2H), 9.11-9.38 (br, 2H).
Example 87
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide
##STR00093##
[0804] A solution of 2-phenyl-pyrimidine-5-carboxylic acid
piperazin-1-ylamide dihydrochloride (0.45 mmol) and
bromo-dihydro-furan-2-one (1.8 mmol) in DMF (10 mL) is stirred
under N.sub.2 at 0.degree. C. for 15 min, then NaH (60%, 1.8 mmol)
is added and the mixture is warmed to rt and stirred overnight. The
mixture is quenched with water, and extracted with EtOAC. The
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 0-2% methanol in DCM to afford give
2-phenyl-pyrimidine-5-carboxylic acid
[4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide (120 mg,
73%) as a solid. MS: 368 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 2.34 (s, 2H), 2.50-3.30 (m, 8H), 3.42-3.70 (m, H),
4.17-4.50 (m, 2H), 7.34-7.68 (m, 3H), 8.50 (d, 2H), 9.06-9.38 (d,
2H). IC.sub.50=26 nM.
Example 88
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-amide
##STR00094##
[0806] A solution of 2-phenyl-pyrimidine-5-carboxylic acid
piperazin-1-ylamide dihydrochloride (0.36 mmol), trifluoroacetic
anhydride (1.08 mmol) and Et.sub.3N (1.44 mmol) in DMF (8 mL) is
stirred under N.sub.2 at rt overnight. The reaction mixture is
concentrated in vacuo. The residue is dissolved in EtOAc (15 mL),
washed with water (10 ml) and brine (15 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is triturated with ether to give 2-phenyl-pyrimidine-5-carboxylic
acid [4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-amide (136 mg,
100%) as a solid. MS: 380 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 2.95-3.40 (s, 4H), 3.60-4.10 (m, 4H), 7.41-7.68 (m, 3H),
8.52 (d, 2H), 9.03-9.40 (br, 2H). IC.sub.50=57 nM.
Example 89
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-methoxy-ethyl)-piperazin-1-yl]-amide
##STR00095##
[0808] Step 1: To a suspended solution of
2-phenyl-pyrimidine-5-carboxylic acid
[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide (0.83 mmol) in DCM (8
mL) under N.sub.2 are added a solution of Et.sub.3N (2.67 mmol) in
DCM (1 mL), a solution of N,N-dimethyl-4-aminopyridine (0.2 mmol)
in DCM (1 mL) and a solution of di-tert-butyl dicarbonate (1.48
mmol) in DCM (1 mL) at rt. The resulting mixture is stirred at rt
for 3 h, and then concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 6% ethanol in EtOAc to
afford
[4-(2-methoxy-ethyl)-piperazin-1-yl]-(2-phenyl-pyrimidine-5-carbonyl)-car-
bamic acid tert-butyl ester (70 mg, 20%) as a solid. MS: 428
(M+H).
[0809] Step 2: A solution of
[4-(2-methoxy-ethyl)-piperazin-1-yl]-(2-phenyl-pyrimidine-5-carbonyl)-car-
bamic acid tert-butyl ester (0.21 mmol), NaH (60%, 0.66 mmol) and
iodomethane (0.63 mmol) in DMF (8 mL) is stirred under N.sub.2 at
rt overnight. The reaction mixture is quenched with water, and
extracted with EtOAc. The organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-2% methanol
in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid
[4-(2-methoxy-ethyl)-piperazin-1-yl]-amide (32 mg, 44%) as a solid.
MS: 342 (M+H).
Example 90
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide
##STR00096##
[0811] A solution of 2-phenyl-pyrimidine-5-carboxylic acid
piperazin-1-ylamide dihydrochloride (0.43 mmol) and NaH (60%, 2.15
mmol) in DMF (10 mL) is stirred under N.sub.2 at rt for 20 min.
2-Chloro-1-morpholin-4-yl-ethanone (0.65 mmol)) is added and the
reaction mixture is stirred at rt overnight. The reaction mixture
is quenched with water, and extracted with EtOAc. The organic layer
is separated, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue is purified by silica gel chromatography
eluting with 0-4% methanol in DCM to afford
2-phenyl-pyrimidine-5-carboxylic acid
[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-amide (24 mg,
14%) as a solid. MS: 411 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 2.85-3.10 (m, 2H), 3.60-4.00 (m, 12H), 4.46 (d, 2H), 4.84
(s, 2H), 7.44-7.62 (m, 3H), 8.34-8.58 (m, 2H), 9.20-9.38 (d, 2H).
IC.sub.50=831.5 nM.
Example 91
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00097##
[0813] Following procedures similar to those of Example 64 but
substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid for
2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (83%) as a solid. MS: 335 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.00 (s, 2H), 3.70 (s,
2H), 6.53-7.34 (m, 5H), 7.45 (s, H), 8.00-8.38 (m, 2H), 9.20 (s,
2H). IC.sub.50=3 nM.
Example 92
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide
##STR00098##
[0815] Following procedures similar to those of Example 64 but
substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid for
2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
piperadin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
piperadin-1-yl-amide (71%) as a solid. MS: 301 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.20-2.00 (m, 6H), 2.20-3.60 (m,
4H), 6.97-7.30 (m, H), 7.34-7.56 (m, H), 8.06-8.38 (m, 2H),
9.00-9.38 (d, 2H). IC.sub.50=19.5 nM.
Example 93
2-(4-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide,
##STR00099##
[0817] Step 1: Following the procedures similar to those of Example
59, step 1, but substituting 4-methoxyphenylboronic acid for
3-methoxyphenylboronic acid, there is prepared
2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester.
[0818] Step 2: Following the procedures similar to those of Example
59, step 2, but substituting
2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester,
there is prepared 2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic
acid.
[0819] Step 3: Following the procedures similar to those of Example
59, step 3, but substituting
2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic acid for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid, there is
prepared 2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide. MS: 341
(M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.91 (s, 3H), 3.86 (s,
3H), 4.22 (s, 2H), 7.12 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 8.42 (d,
J=8.6 Hz, 1H), 9.21 (s, 2H), 9.95 (s, 1H), 11.02 (s, 1H).
Example 94
2-Phenyl-pyrimidine-5-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide
##STR00100##
[0821] Following procedures similar to those of Example 64 but
substituting hexahydro-cyclopenta[c]pyrrol-2-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide (39%) as a solid. MS:
309 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.20-1.90 (m,
6H), 2.40-3.50 (m, 6H), 6.94 (s, N--H), 7.52 (s, 3H), 8.50 (s, 2H),
9.08-9.38 (d, 2H).
Example 95
4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00101##
[0823] Following procedures similar to those of Example 64 but
substituting 4-methyl-2-phenyl-pyrimidine-5-carboxylic acid
chloride for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and
substituting 2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared there is prepared
4-methyl-2-phenyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (80%) as a solid. MS: 331 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.69 (s, 3H), 2.74-3.10
(m, 2H), 3.64 (t, 2H), 6.58-6.97 (m, 2H), 7.03-7.30 (m, 2H), 7.49
(s, 3H), 7.96 (s, N--H), 8.44 (s, 2H), 8.72 (d, 2H). IC.sub.50=5.5
nM.
Example 96
2-Phenyl-pyrimidine-5-carboxylic acid pyrrolidin-1-yl-amide
##STR00102##
[0825] Following procedures similar to those of Example 64 but
substituting pyrrolidin-1-ylamine hydrochloride for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid pyrrolidin
1-yl-amide (67%) as a solid. MS: 269 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 1.70-2.20 (m, 4H), 2.70-3.46 (m, 4H), 7.55 (s,
3H), 8.42-8.67 (m, 2H), 9.14-9.49 (t, 2H).
Example 97
2-Phenyl-pyrimidine-5-carboxylic acid
(2,6-dimethyl-piperadin-1-yl)-amide
##STR00103##
[0827] Following procedures similar to those of Example 64 but
substituting 2,6-dimethyl-piperadin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (2,6-dimethyl-piperadin-1-yl)-amide (69%) as a solid. MS: 311
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.95-1.24 (m,
6H), 1.24-1.87 (m, 6H), 1.88-3.60 (m, 2H), 6.35 (br, N--H), 7.53
(s, 3H), 8.52 (s, 2H), 9.10-9.73 (m, 2H).
Example 98
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl)-amide
##STR00104##
[0829] Following procedures similar to those of Example 64 but
using substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
4-cyclopentyl-piperazin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(4-cyclopentyl-piperazin-1-yl-amide (64%) as a solid. MS: 370
(M+H).
Example 99
2-Phenyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide
##STR00105##
[0831] Following procedures similar to those of Example 64 but
substituting 2-methyl-2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (2-methyl-2,3-dihydro-indol-1-yl)-amide (32%) as a solid. MS:
331 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.05 (m, 3H),
2.50-2.79 (m, H), 3.03-3.24 (m, H), 3.40-3.58 (m, 0.5H), 3.92 (br,
0.5H), 6.67 (d, 0.5N--H), 6.77-7.33 (m, 4H), 7.51 (m, 3H), 7.98 (s,
0.5N--H), 8.52 (m, 2H), 9.23 (d, 2H). IC.sub.50=4 nM.
Example 100
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide
##STR00106##
[0833] Following procedures similar to those of Example 64 but
substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid for
2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
2-methyl-2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide (31%) as a solid. MS: 349
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.00-1.48 (m,
3H), 2.43-2.78 (m, 2H), 3.32-4.06 (m, H), 6.50-6.93 (m, 1.5H),
6.93-7.34 (m, 4H), 7.34-7.54 (d, H), 8.05-8.32 (m, 2H), 8.56 (s,
0.5N--H), 9.17 (d, 2H). IC.sub.50=4 nM.
Example 101
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-pyridin-2-yl-hydrazide
##STR00107##
[0835] Following procedures similar to those of Example 64 but
substituting N'-methyl-N'-pyridin-2-yl-hydrazine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid N'-methyl-N'-pyridin-2-yl-hydrazide (31%) as a solid. MS: 306
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.48 (s, 3H),
6.88 (m, 2H), 7.40-7.70 (m, 4H), 8.23 (s, H), 8.52 (m, 2H), 9.13
(br, N--H), 9.28 (s, 2H).
Example 102
2-Phenyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00108##
[0837] Step 1: A solution of 5-fluoro-1H-indole (16.9 mmol) and
potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt
under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl. in ether (169.2 mL) is
added drop-wise for 15 minutes at rt. The reaction mixture is
stirred at rt for 2 h, then quenched with 10%
Na.sub.2S.sub.2O.sub.3 aqueous solution and extracted with ether.
The organic layer is separated, dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 60-80% EtOAc in heptane to afford
5-fluoro-indole-1-ylamine (751 mg, 30%) as a solid. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 4.80 (br, 2N--H), 6.38 (d, H), 7.00
(m, H), 7.19-7.43 (m, 3H).
[0838] Step 2: Diethyl-iso-propylamine (2.30 mmol) is added to a
stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride
(1.15 mmol) and 5-fluor-indol-1-ylamine (1.15 mmol) in DCM (20 mL)
at rt. The reaction mixture is stirred at rt overnight and
concentrated in vacuo. The residue is dissolved in EtOAc (30 mL),
then washed with 5% HCl (10 mL), water (10 mL) and brine (10 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with
10-40% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic
acid (5-fluoro-indol-1-yl)-amide (185 mg, 49%) as a solid. MS: 333
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.56 (s, H) 7.02
(m, H), 7.10-7.38 (m, 4H), 7.55 (s, 3H), 8.53 (s, 2H), 8.70-9.40
(br, 2H). IC.sub.50=3 nM.
Example 103
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00109##
[0840] Following procedures similar to those of Example 64 but
substituting 2-pyridin-2-yl-pyrimidine-5-carboxylic acid for
2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (98%) as a solid. MS: 318 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.85-3.20 (m, 2H), 3.77
(t, 2H), 6.76 (d, 0.5N--H), 6.82-7.49 (m, 4H), 7.46 (d, H), 7.89
(d, H), 8.07 (br, 0.5N--H), 8.57 (m, H), 8.84 (d, H), 9.30 (s, 2H).
IC.sub.50=3 nM.
Example 104
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid indol-1-yl-amide
##STR00110##
[0842] A suspended solution of
2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (0.28 mmol) and MnO.sub.2 (1.42
mmol) in DCM (8 mL) is stirred at rt for 2 h. The reaction mixture
is filtered and the filtrate is concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-5% methanol
in DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
indol-1-yl-amide (45 mg, 50%) as a solid. MS: 316 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 6.48 (s, H), 6.72-7.48 (m, 5H),
7.56 (s, H), 7.88 (s, H), 8.52 (br, 2H), 9.08 (br, 2H), 11.56 (br,
N--H). IC.sub.50=4.5 nM.
Example 105
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
indol-1-yl-amide
##STR00111##
[0844] A suspended solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (0.39 mmol) and MnO.sub.2 (1.95
mmol) in DCM (10 mL) is stirred at rt for 40 min. The reaction
mixture is filtered and the filtrate is concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-40%
EtOAc in heptane to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic indol-1-yl-amide (70
mg, 54%) as a solid. MS: 333 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 6.60 (s, H), 7.10 (d, H), 7.14-7.46 (m, 4H),
7.50 (br, H), 7.64 (d, H), 8.37 (d, 2H), 8.60-9.40 (br, 3H).
IC.sub.50=5 nM.
Example 106
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00112##
[0846] Following procedures similar to those of Example 64 but
substituting 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and
substituting 2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (91%) as a solid. MS: 349 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.77-3.08 (m, 2H),
3.09-3.80 (m, 2H), 6.75-7.00 (m, 2H), 7.04-7.32 (m, 3H), 7.44 (q,
H), 8.06-8.31 (m, 2H), 8.51 (d, 2H). IC.sub.50=23 nM.
Example 107
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide
##STR00113##
[0848] Following procedures similar to those of Example 64 but
substituting 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and
substituting 2-methyl-2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide (94%) as a solid. MS: 363
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.00-1.50 (d,
3H), 2.30-2.80 (m, 4H), 3.01 (m, H), 3.26-3.96 (m, H), 6.45-7.00
(m, 2H), 7.00-7.30 (m, 3H), 7.41 (q, H), 7.97-8.28 (m, 2H), 8.68
(d, H).
Example 108
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide
##STR00114##
[0850] A suspended solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide (0.98 mmol) and MnO.sub.2
(4.88 mmol) in DCM (15 mL) is stirred at rt for 2 h. The reaction
mixture is filtered and the filtrate is concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-40%
EtOAc in heptane to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide (230 mg, 97%) as a solid. MS: 347
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.08-2.40 (m,
3H), 6.27 (s, H), 6.95-7.35 (m, 4H), 7.36-7.65 (m, 2H), 8.20-8.44
(m, 2H), 8.49-9.20 (d, 2H). IC.sub.50=6 nM.
Example 109
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
indol-1-ylamide
##STR00115##
[0852] A suspended solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (0.72 mmol) and MnO.sub.2 (3.60
mmol) in DCM (10 mL) is stirred at rt for 40 min. The reaction
mixture is filtered and the filtrate is concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-40%
EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
indol-1-ylamide (185 mg, 75%) as a solid. MS: 347 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 2.73 (s, 3H), 6.53 (s, H), 7.03
(d, H), 7.08-7.36 (m, 4H), 7.37-7.75 (m, 2H), 8.04-8.40 (m, 2H),
8.56 (br, H), 8.81 (br, H). IC.sub.50=10 nM.
Example 110
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide
##STR00116##
[0854] Following procedures similar to those of Example 64 but
substituting 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting
2,3-dihydro-indol-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (96%) as a solid. MS: 332 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.78 (s, 3H), 3.09 (t,
2H), 3.77 (t, 2H), 6.70-7.01 (m, 2H), 7.09-7.23 (m, 2H), 7.36-7.46
(m, H), 7.85 (t, H), 8.43-8.64 (m, 2H), 8.80 (d, H). IC.sub.50=3
nM.
Example 111
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
indol-1-ylamide
##STR00117##
[0856] A suspended solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(2,3-dihydro-indol-1-yl)-amide (1.00 mmol) and MnO.sub.2 (5.00
mmol) in DCM (10 mL) is stirred at rt for 60 min. The reaction
mixture is filtered and the filtrate is concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-5%
methanol in DCM to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
indol-1-ylamide (196 mg, 60%) as a solid. MS: 330 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 2.77 (s, 3H), 6.58 (s, H), 7.15
(s, 2H), 7.26 (m, 3H), 7.84 (d, H), 8.44 (s, 2H), 8.73 (s, H),
10.94 (br, N--H). IC.sub.50=5 nM.
Example 112
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide
##STR00118##
[0858] Step 1: A solution of 5-methanesulfonyl-indoline (4.11 mmol)
and MnO.sub.2 (20.55 mmol) in DCM (20 mL) is stirred at rt
overnight. The reaction mixture is filtered and the filtrate is
concentrated in vacuo to afford 5-methanesulfonyl-1H-indole (782
mg, 100%) as a solid. MS: 196 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 3.09 (s, 3H), 6.71 (s, H), 7.39 (s, H), 7.53
(d, H), 7.74 (m, H), 8.30 (s, H), 8.66 (br, N--H).
[0859] Step 2: A solution of 5-methanesulfonyl-1H-indole (4.1 mmol)
and potassium tert-butoxide (8.2 mmol) in DMF (20 mL) is stirred at
rt under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl in ether (41 mL) is
added drop-wise for 15 min at rt and the reaction mixture is
stirred at rt for 2 h. The reaction mixture is quenched with 10%
Na.sub.2S.sub.2O.sub.3 aqueous solution, and extracted with ether
(3.times.40 mL). The combined organic layer is washed with water
(2.times.30 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with EtOAc and heptane to afford
5-methanesulfonyl-indole-1-ylamine (230 mg, 32%) as a solid. MS:
211 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.08 (s, 3H),
4.94 (br, 2N--H), 6.55 (d, H), 7.34 (m, H), 7.57 (d, H), 7.73 (m,
H), 8.21 (m, H).
[0860] Step 3: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.62
mmol) in EtOAc (10 mL) is added to a stirred solution of
5-methanesulfonyl-indole-1-ylamine (0.62 mmol) and K.sub.2CO.sub.3
(3.08 mmol) in EtOAc (10 mL) and H.sub.2O (10 mL) at 0.degree. C.,
and the reaction mixture is warmed to rt and stirred overnight.
EtOAc is evaporated in vacuo, and the resulting solid is collected
by filtration. The solid is triturated with DCM to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide (85 mg, 34%) as a solid. MS:
411 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.13 (s, 3H),
6.81 (m, H) 7.25-7.39 (m, H), 7.49-7.67 (m, 3H), 7.72-7.84 (m, H),
8.21-8.32 (m, 2H), 8.39 (d, H), 9.41 (s, 2H).
Example 113
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methanesulfonyl-indol-1-yl)-amide
##STR00119##
[0862] Step 1: A solution of 6-methanesulfonyl-1H-indole (2.66
mmol) and potassium tert-butoxide (5.32 mmol) in DMF (15 mL) is
stirred at rt under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl in ether
(26.6 mL) is added drop-wise for 15 minutes at rt and the reaction
mixture is stirred at rt for 2 h. The reaction mixture is quenched
with 10% Na.sub.2S.sub.2O.sub.3 aqueous solution, and extracted
with ether (3.times.20 mL). The combined organic layer is washed
with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is triturated with EtOAc to give
6-methanesulfonyl-indole-1-ylamine (270 mg, 51%) as a solid. MS:
211 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.09 (s, 3H),
6.49 (d, H), 7.41 (m, H), 7.61 (d, H), 7.71 (d, H), 8.12 (s,
H).
[0863] Step 2: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.65
mmol) in EtOAc (15 mL) is added to a stirred solution of
5-methanesulfonyl-indole-1-ylamine (0.65 mmol) and potassium
carbonate (2.60 mmol) in EtOAc (10 mL) and H.sub.2O (10 mL) at
0.degree. C., and the reaction mixture is warmed to rt and stirred
overnight. EtOAc is evaporated in vacuo, and the resulting solid is
collected by filtration, and purified by silica gel chromatography
eluting with 20-60% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-methanesulfonyl-indol-1-yl)-amide (85 mg, 33%) as a solid. MS:
411 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.08 (s, 3H),
6.62 (d, H) 7.33-7.44 (m, 2H), 7.46-7.59 (m, 2H), 7.75 (s, H), 8.29
(d, 2H), 8.39 (d, H), 9.42 (s, 2H), 10.80 (br, H). IC.sub.50=8
nM.
Example 114
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide
##STR00120##
[0865] Diethyl-iso-propylamine (3.54 mmol) is added a solution of
2-pyridin-2-yl-pyrimidine-5-carboxylic acid HCl (1.18 mmol),
5-methanesulfonyl-indol-1-ylamine (1.18 mmol) and TBTU (1.77 mmol)
in anhydrous DMF (16 mL) at rt. The reaction mixture is stirred at
90.degree. C. overnight and then concentrated in vacuo. The residue
is dissolved in EtOAc (50 mL) and water (50 mL). The organic layer
is separated, washed with water (2.times.20 mL) and brine (20 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residue is triturated with EtOAc and DCM to afford
2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide (125 mg, 27%) as a solid. MS:
394 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.14 (s, 3H),
6.82 (m, H) 7.50-7.72 (m, 3H), 7.80 (m, H), 8.07 (m, H), 8.30 (m,
2H), 8.70 (d, H), 8.80 (s, H), 9.51 (s, 2H).
Example 115
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide
##STR00121##
[0867] Diethyl-iso-propylamine (3.84 mmol) is added a solution of
2-pyridin-2-yl-pyrimidine-5-carboxylic acid hydrochloride (1.28
mmol), 5-methanesulfonyl-indol-1-ylamine (1.28 mmol) and TBTU (1.92
mmol) in anhydrous DMF (16 mL) at rt. The reaction mixture is
stirred at 90.degree. C. overnight and then concentrated in vacuo.
The residue is dissolved in EtOAc (60 mL), and washed with water
(2.times.30 mL) and brine (20 mL), The organic layer is separated,
washed with water (2.times.20 mL) and brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-5% MeOH in
DCM to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide (125 mg, 25%) as a solid. MS:
394 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.10 (s, 3H),
6.61 (m, H) 6.98 (m, H), 7.34 (s, H), 7.51 (m, H), 7.91 (s, H),
8.83 (m, 2H), 9.49 (s, H), 9.77 (s, H), 10.10 (s, N--H).
Example 116
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide
##STR00122##
[0869] 2.0 M of NaHMDS (sodium bis(trimethylsilyl)amide) in THF is
added to a stirred solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride
(0.72 mmol) and 5-methanesulfonyl-indol-1-ylamine (0.72 mmol) and
in anhydrous pyridine (10 mL) at rt. The reaction mixture is
stirred at 90.degree. C. overnight and then concentrated in vacuo.
The residue is purified ny silica gel chromatography eluting with
1.5% MeOH in DCM to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-indol-1-yl)-amide (50 mg, 8%) as a solid. MS:
425 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.86 (s, 3H),
3.02 (s, 3H), 6.55 (s, H) 6.92 (d, H), 7.17-7.38 (m, 3H), 7.53 (m,
H), 7.78 (s, H), 8.27 (d, H), 8.38 (d, H), 9.16 (s, H).
Example 117
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide
##STR00123##
[0871] Step 1: A solution of pyrrolo[2,3-b]pyridine (16.9 mmol) and
potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt
under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl in ether (169.2 mL) is
added drop-wise at rt and the reaction mixture is stirred at rt for
2 h. The reaction mixture is quenched with 5%
Na.sub.2S.sub.2O.sub.3 aqueous solution (100 mL), and extracted
with ether for three times. The combined organic layer is washed
with brine (20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 60-80% EtOAc in heptane to afford
pyrrolo[2,3-b]pyridin-1-ylamine (703 mg, 31%) as a solid. MS: 134
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 5.04 (br, 2N--H),
6.35 (d, H), 7.09 (m, H), 7.35 (m, H), 7.91 (m, H), 8.34 (d,
H).
[0872] Step 2: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1.13
mmol) in EtOAc (20 mL) is added to a stirred solution of
pyrrolo[2,3-b]pyridin-1-ylamine (1.13 mmol) and K.sub.2CO.sub.3
(1.13 mmol) in EtOAc (10 mL) and H.sub.2O (20 mL) at rt and the
reaction mixture is stirred at rt overnight. EtOAc is evaporated in
vacuo, and the resulting solid is collected by filtration to afford
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide (305 mg, 81%) as a solid. MS: 334
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.57 (d, H)
7.13-7.55 (m, 4H), 7.99 (m, H), 8.10-8.40 (m, 3H), 9.27 (s, 2H),
12.57 (br, N--H).
Example 118
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide
##STR00124##
[0874] Step 1: A solution of pyrrolo[3,2-b]pyridine (1.64 mmol) and
potassium tert-butoxide (3.29 mmol) in DMF (7.3 mL) is stirred at
rt under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl. in ether (16.3 mL) is
added drop-wise at rt and the reaction mixture is stirred at rt for
3 h. The reaction mixture is quenched with 5%
Na.sub.2S.sub.2O.sub.3 aqueous solution (10 mL), and extracted with
ether. The combined organic layer is washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with EtOAc to
afford pyrrolo[3,2-b]pyridin-1-ylamine (136 mg, 62%) as a solid.
MS: 134 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.89 (br,
2N--H), 6.61 (d, H), 7.16 (m, H), 7.38 (d, H), 7.76 (d, H), 8.47
(d, H).
[0875] Step 2: A solution of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.45
mmol) in EtOAc (8 mL) is added to a stirred solution of
pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and K.sub.2CO.sub.3
(0.45 mmol) in EtOAc (4 mL) and H.sub.2O (8 mL) at rt, and the
reaction mixture is stirred at rt for 30 min. EtOAc is evaporated
in vacuo, and the resulting solid is collected by filtration to
afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide (116 mg, 77%) as a solid. MS: 334
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.60 (d, H)
7.15-7.60 (m, 4H), 8.01 (m, H), 8.10-8.41 (m, 3H), 9.27 (s, 2H),
12.45 (br, N--H). IC.sub.50=18 nM.
Example 119
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00125##
[0877] A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred
solution of 5-fluoro-indol-1-ylamine (1 mmol) and potassium
carbonate (1 mmol) in EtOAc (10 mL) and H.sub.2O (20 mL) at rt and
the reaction mixture is stirred at rt overnight. EtOAc is
evaporated in vacuo, and the resulting solid is collected by
filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid (5-fluoro-indol-1-yl)-amide (148 mg, 42%) as a solid. MS: 351
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.56 (m, H) 7.02
(m, H), 7.12-7.34 (m, 3H), 7.51 (m, H), 8.24 (d, H), 8.34 (s, H),
8.92 (br, H), 9.24 (br, 2H).
Example 120
2-(2-Methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00126##
[0879] Step 1: Following the procedures similar to those of Example
59, step 1, but substituting 2-methoxyphenylboronic acid for
3-methoxyphenylboronic acid, there is prepared
2-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester.
[0880] Step 2: Following the procedures similar to those of Example
59, step 2, but substituting
2-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester,
there is prepared 2-(2-methoxy-phenyl)-pyrimidine-5-carboxylic
acid.
[0881] Step 3: Following the procedures similar to those of Example
59, step 3, but substituting
2-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid, there is
prepared 2-(2-methoxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide. MS: 341
(M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.91 (s, 3H), 3.79 (s,
2H), 4.22 (s, 2H), 7.09 (m, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.52 (m,
1H), 7.65 (m, 1H), 9.24 (s, 2H), 9.96 (s, 1H), 11.06 (s, 1H).
IC.sub.50=199 nM.
Example 121
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide
##STR00127##
[0883] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride
(0.45 mmol) in EtOAc (8 mL) is added to a stirred solution of
pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and potassium carbonate
(0.45 mmol) in EtOAc (4 mL) and H.sub.2O (8 mL) at rt and the
reaction mixture is stirred at rt overnight. EtOAc is evaporated in
vacuo, and the resulting solid is collected by filtration. The
solid is purified by silica gel chromatography eluting with 20-80%
EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide (38 mg, 24%) as a solid. MS: 348
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.76 (s, 3H),
6.59 (m, H) 7.07-7.64 (m, 4H), 7.96 (m, H), 8.23 (m, H), 8.32 (m,
2H), 9.12 (s, H), 10.01 (br, N--H).
Example 122
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide
##STR00128##
[0885] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride
(1 mmol) in EtOAc (10 mL) is added to a stirred solution of
pyrrolo[2,3-b]pyridin-1-ylamine (1 mmol) and K.sub.2CO.sub.3 (1
mmol) in EtOAc (20 mL) and H.sub.2O (20 mL) at rt, then stirred at
rt overnight. EtOAc is evaporated in vacuo, and the resulting solid
is collected by filtration. The solid is purified by silica gel
chromatography eluting with 20-80% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide (162 mg, 47%) as a solid. MS: 348
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.78 (s, 3H),
6.59 (m, H) 7.09-7.58 (m, 4H), 7.96 (m, H), 8.22 (m, H), 8.31 (d,
2H), 9.14 (s, 2H). IC.sub.50=12 nM.
Example 123
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00129##
[0887] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1
mmol) in EtOAc (20 mL) is added to a stirred solution of
5-fluoro-indol-1-ylamine (1.20 mmol) and K.sub.2CO.sub.3 (2 mmol)
in EtOAc (10 mL) and H.sub.2O (20 mL) at rt, and the reaction
mixture is stirred at rt overnight. The reaction mixture is
extracted with EtOAc. The organic layer is washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-10% MeOH in
DCM to give a solid. The solid is triturated with EtOAc/heptane to
afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (122 mg, 35%) as a solid. MS: 348
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.77 (s, 3H),
6.55 (m, H) 7.06 (m, H), 7.32-7.66 (m, 4H), 8.02 (m, H), 8.45 (d,
H), 8.79 (s, H), 9.26 (s, H), 12.00 (s, N--H). IC.sub.50=17 nM.
Example 124
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00130##
[0889] A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution
of 5-fluoro-indol-1-ylamine (1 mmol) and K.sub.2CO.sub.3 (2 mmol)
in EtOAc (10 mL) and H.sub.2O (20 mL) at rt, and the reaction
mixture is stirred at rt overnight. EtOAc is evaporated in vacuo,
and the resulting solid is collected by filtration. The solid is
purified by silica gel chromatography eluting with 0-10% MeOH in
DCM to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (65 mg, 20%) as a solid. MS: 334 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 6.56 (m, H) 7.04 (m, H),
7.28-7.79 (m, 3H), 8.04 (m, H), 8.49 (m, H), 8.81 (m, H), 9.48 (s,
2H), 12.22 (s, N--H). IC.sub.50=18 nM.
Example 125
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridine-1-ylamide
##STR00131##
[0891] Diethyl-iso-propylamine (1.13 mmol) is added a solution of
2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol),
pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU in anhydrous
DMF (7 mL) at rt, and the reaction mixture is stirred at 80.degree.
C. overnight. The reaction mixture is concentrated in vacuo. The
residue is dissolved in EtOAc, washed with water twice, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 10% MeOH in
DCM to give a crude product. The product is crystallized from EtOAc
to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridine-1-ylamide (78 mg, 25%) as a solid. MS: 317
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 6.56 (m, H) 7.24
(m, H), 7.53 (m, H), 7.61 (m, H), 8.01-8.17 (m, 2H), 8.27 (d, H),
8.69 (m, H), 8.78 (m, H), 9.51 (s, 2H).
Example 126
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide
##STR00132##
[0893] Diethyl-iso-propylamine (1.13 mmol) is added a solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol),
pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in
anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at
80.degree. C. overnight. The reaction mixture is concentrated in
vacuo. The residue is dissolved in EtOAc, washed with saturated
aqueous Na.sub.2CO.sub.3 and water, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 10% CH.sub.3CN in DCM to
give a crude product. The crude product is crystallized from EtOAc
to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrol[2,3-b]pyridine-1-ylamide (95 mg, 38%) as a solid. MS: 331
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.89 (s, 3H),
6.65 (d, H), 7.23 (m, H), 7.48-7.66 (m, 2H), 8.01-8.15 (m, 2H),
8.29 (m, H), 8.64 (d, H), 8.77 (d, H), 9.33 (s, 2H).
Example 127
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide
##STR00133##
[0895] Diethyl-iso-propylamine (1.88 mmol) is added a solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol),
pyrrolo[3,2-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in
anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at
80.degree. C. for 8 h. The reaction mixture is concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 0-10% MeOH in DCM to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrol[3,2-b]pyridine-1-ylamide (155 mg, 63%) as a solid. MS: 331
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.89 (s, 3H),
7.01 (d, H), 7.64-7.77 (m, 2H), 8.15 (m, H), 8.25 (m, H), 8.59-8.76
(m, 3H), 8.82 (d, H), 9.31 (s, 2H). IC.sub.50=13 nM.
Example 128
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide
##STR00134##
[0897] Step 1: A solution of pyrrolo[2,3-c]pyridine (8.47 mmol) and
potassium tert-butoxide (16.9 mmol) in DMF (38 mL) is stirred at rt
under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl in ether (84.6 mL) is
added drop-wise at rt, and the reaction mixture is stirring at rt
for 2 h., quenched with 5% Na.sub.2S.sub.2O.sub.3 aqueous solution
(10 mL), and extracted with ether. The organic layer is separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 0-10% MeOH in DCM to afford pyrrolo
[2,3-c]pyridin-1-ylamine (226 mg, 11%) as a solid. MS: 134 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.96 (br, 2N--H), 6.43
(d, H), 7.29 (m, H), 7.50 (d, H), 8.29 (d, H), 8.89 (s, H).
[0898] Step 2: Diethyl-iso-propylamine (1.13 mmol) is added a
solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid (0.75 mmol), pyrrolo[2,3-c]pyridine-1-ylamine (0.75 mmol) and
TBTU (0.9 mmol) in anhydrous DMF (7 mL) at rt, and the reaction
mixture is stirred at 80.degree. C. overnight. Water is added and
the mixture is extracted with EtOAc. The organic layer is
separated, washed with water and brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 40-100% MeOH in DCM to
afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide (117 mg, 45%) as a solid. MS: 348
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.84 (s, 3H),
6.72 (d, H), 7.29 (m, H), 7.55 (m, H), 7.71 (m, H), 8.14-8.29 (m,
2H), 8.36 (d, 3), 8.75 (s, H), 9.17 (s, H). IC.sub.50=28.5 nM.
Example 129
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide
##STR00135##
[0900] Following procedures similar to those of Example 127 but
substituting pyrrolo[2,3-c]pyridine-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrol[2,3-c]pyridine-1-ylamide (46%) as a solid. MS: 331 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.79 (s, 3H), 6.64 (d,
H), 7.53-7.65 (m, 2H), 7.78 (d, H), 8.02 (m, H), 8.22 (m, H), 8.46
(m, H), 8.80 (d, H), 8.87 (s, H), 9.30 (s, H).
Example 130
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-b]pyridin-1-ylamide
##STR00136##
[0902] Following procedures similar to those of Example 127 but
substituting 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
for 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, there is
prepared 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
pyrrolo [32-b]pyridine-1-ylamide (40%) as a solid. MS: 331 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.86 (s, 3H), 6.74 (m,
H), 7.31 (m, H), 7.61 (m, H), 7.71 (d, H), 7.92 (d, H), 8.41 (d,
H), 8.71 (d, H), 8.91 (d, H), 9.20 (s, H), 9.64 (s, H).
IC.sub.50=14 nM.
Example 131
4-Methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00137##
[0904] Following procedures similar to those of Example 127 but
substituting 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid
for 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and
substituting 5-fluoro-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (34%) as a solid. MS: 348 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.85 (s, 3H), 6.57 (m,
H), 7.02 (m, H), 7.23-7.46 (m, 2H), 7.62 (m, H), 8.70 (d, H), 8.91
(d, H), 9.17 (s, H), 9.63 (s, H).
Example 132
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide
##STR00138##
[0906] Method A: Following procedures similar to those of Example
127 but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and
substituting 5-fluoro-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (17%) as a solid. MS: 365 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 6.56 (d, H), 7.02 (m,
H), 7.22-7.44 (m, 4H), 7.55 (m, H), 8.22 (d, H), 8.36 (d, H), 9.13
(s, H).
[0907] Method B: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride
(1 mmol) in EtOAc (20 mL) is added to a stirred solution of
5-fluoro-indol-1-ylamine (1 mmol) and K.sub.2CO.sub.3 (1 mmol) in
EtOAc (10 mL) and H.sub.2O (20 mL) at rt, then stirred at rt
overnight. EtOAc is evaporated in vacuo, and the resulting solid is
collected by filtration. The solid is crystallized from
EtOAc/heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (62 mg, 17%) as a solid. MS: 365 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.82 (s, H), 6.55 (s, H)
6.90-7.41 (m, 4H), 7.49 (m, H), 8.26 (d, 2H), 8.57 (br, H), 8.96
(br, H). IC.sub.50=19 nM.
Example 133
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide
##STR00139##
[0909] Step 1: A solution of 5-methoxy-1H-indole (16.9 mmol) and
potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt
under N.sub.2 for 2 h. 0.15 M NH.sub.2Cl in ether (169.2 mL) is
added drop-wise for 15 minutes at rt. The reaction mixture is
stirred at rt for 2 h, quenched with 5% Na.sub.2S.sub.2O.sub.3
aqueous solution (100 mL), and stirred at rt overnight. The mixture
is extracted with ether. The organic layer is separated, washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 0-20% EtOAc in heptane to afford 5-methoxy-indole-1-ylamine
(388 mg, 14%) as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 4.78 (br, 2N--H), 6.35 (d, H), 6.94 (d, H), 7.08 (d, H),
7.17 (d, H), 7.30-7.39 (d, H).
[0910] Step 2: Following procedures similar to those of Example 127
but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and
substituting 5-methoxy-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide (43%) as a solid. MS: 377 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.83 (s, 3H), 3.84 (s,
3H), 6.50 (d, H), 6.90 (m, H), 7.12 (d, H), 7.22-7.36 (m, 3H), 7.55
(m, H), 8.22 (d, H), 8.36 (d, H), 9.11 (s, H). IC.sub.50=6 nM.
Example 134
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-cyano-indol-1-yl)-amide
##STR00140##
[0912] Step 1: NaH (60%, 60 mmol) is portion-wise added to a
solution of 5-cyano-1H-indole (20 mmol) in NMP (35 mL), and the
reaction mixture is 0.degree. C. for 1 h. A solution of HOSA (60
mmol) in NMP (14 mL) is added drop-wise at 0.degree. C. The
reaction mixture is warmed to rt and stirred overnight, then
quenched with water and extracted with EtOAc. The organic layer is
separated, washed with water three times and with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 20-40% EtOAc
in heptane to afford 5-cyano-indole-1-ylamine (531 mg, 16%) as a
solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.88 (br, 2N--H),
6.53 (d, H), 7.32 (d, H), 7.54 (q, 2H), 7.98 (d, H).
[0913] Step 2: Following procedures similar to those of Example 127
but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and
substituting 5-cyano-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-cyano-indol-1-yl)-amide (39%) as a solid. MS: 372 (M+H); .sup.1H
NMR (300 MHz, DMSO-d.sup.6): .delta. 2.77 (s, 3H), 6.73 (d, H),
7.45 (m, H), 7.53-7.82 (m, 4H), 8.08-8.23 (m, 2H), 8.32 (d, H),
9.27 (s, H), 12.15 (br, N--H).
Example 135
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(4-cyano-indol-1-yl)-amide
##STR00141##
[0915] Step 1: Following procedures similar to those of Example
134, step 1, but substituting 4-cyano-1H-indole for
5-cyano-1H-indole, there is prepared 4-cyano-indole-1-ylamine (33%)
as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.1 (br,
2N--H), 6.88 (d, H), 7.22-7.40 (m, 2H), 7.51 (d, H), 7.72 (d,
H).
[0916] Step 2: Following procedures similar to those of Example
127, but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and
substituting 4-cyano-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(4-cyano-indol-1-yl)-amide (29%) as a solid. MS: 372 (M+H); .sup.1H
NMR (300 MHz, DMSO-d.sup.6): .delta. 2.77 (s, 3H), 6.71 (s, H),
7.32-7.51 (m, 2H), 7.57-7.69 (m, 2H), 7.88 (m, 2H), 8.16 (d, H),
8.31 (d, H), 9.25 (s, H).
Example 136
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[4-(1H-tetrazol-5-yl)-indol-1-yl]-amide
##STR00142##
[0918] A solution of (0.5 mmol), ammonia chloride (6 mmol) and
sodium azide (6 mmol) in anhydrous DMF (6 mL) is heated in the
microwave at 200.degree. C. for 1 h. The reaction mixture is
quenched with saturated aqueous Na.sub.2CO.sub.3 solution, and
washed with EtOAc. The aqueous layer is separated, acidified with
concentrated aqueous HCl to adjust pH to 1, and extracted with
EtOAc. The organic layer is separated, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 3% MeOH in DCM to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[4-(1H-tetrazol-5-yl)-indol-1-y]-amide (18 mg, 9%) as a solid. MS:
415 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.85 (s, 3H),
7.20-7.35 (m, 2H), 7.44 (m, H), 7.52-7.59 (m, 2H), 7.65 (m, H),
7.77 (d, H), 8.23 (d, H), 8.37 (d, H), 9.18 (s, H).
Example 137
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4--
carboxylic acid methyl ester
##STR00143##
[0920] Step 1: Following procedures similar to those of Example
133, step 1, but substituting 1H-indole-4-carboxylic acid methyl
ester for 5-methoxy-1H-indole, there is prepared
1-amino-1H-indole-4-carboxylic acid methyl ester (10%) as a solid.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.88 (br, 2N--H), 7.03
(d, H), 7.33 (m, 2H), 7.49 (d, H), 7.94 (d, H).
[0921] Step 2: Following procedures similar to those of Example
127, but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, substituting
1-amino-1H-indole-4-carboxylic acid methyl ester for
pyrrolo[3,2-b]pyridine-1-ylamine, and the reaction is stirred at
15.degree. C. for 45 minutes, there is prepared
1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid methyl ester (33%) as a solid. MS: 405 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sup.6): .delta. 2.77 (s, 3H), 3.92 (s,
3H), 7.44 (m, H), 7.63 (m, H), 7.72 (m, H), 7.76-7.88 (m, 2H), 8.17
(d, H), 8.31 (d, H), 9.26 (s, H), 12.06 (br, N--H).
Example 138
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4--
carboxylic acid
##STR00144##
[0923] A solution of
1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid methyl ester (0.48 mmol) and LiOH (1.91 mmol) in
Methanol/THF/H.sub.2O (1:1:1, 6 mL) is stirred at rt overnight. The
reaction mixture is diluted with water and washed with DCM. The
aqueous layer is separated and acidified with 10% aqueous HCl to
adjust pH to 1. The mixture is extracted with ether twice. The
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford
1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-4-
-carboxylic acid (186 mg, 99%) as a solid. MS: 391 (M+H); .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 2.85 (s, 3H), 7.20 (m, H),
7.24-7.40 (m, 2H), 7.46-7.61 (m, 2H), 7.66 (d, H), 7.92 (d, H),
8.23 (d, H), 8.37 (d, H), 9.16 (s, H).
Example 139
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyanomethyl-indol-1-yl)-amide
##STR00145##
[0925] Step 1: Following procedures similar to those of Example
133, step 1, but substituting 1H-indol-3-yl-acetonitrile for
5-methoxy-1H-indole, there is prepared
(1-amino-1H-indol-3-yl)-acetonitrile (17%) as a solid. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 3.83 (s, 2H), 4.80 (br, 2N--H),
7.17-7.25 (m, 2H), 7.33 (t, H), 7.46 (d, H), 7.59 (d, H).
[0926] Step 2: Following procedures similar to those of Example
127, but substituting
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid for
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, substituting
3-cyanomethyl-indol-1-ylamine for pyrrolo[3,2-b]pyridine-1-ylamine,
and the reaction is stirred at 150.degree. C. for 1 h, there is
prepared 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-cyanomethyl-indol-1-yl)-amide (42%) as a solid. MS: 386 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.84 (s, 3H), 4.03 (s,
2H), 7.15-7.48 (m, 5H), 7.55 (m, H), 7.70 (d, H), 8.23 (d, H), 8.37
(d, H), 9.14 (s, H).
Example 140
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide
##STR00146##
[0928] Following procedures similar to those of Example 127, but
substituting 5-methoxy-indol-1-ylamine for
pyrrolo[3,2-b]pyridine-1-ylamine, and the reaction is stirred at
150.degree. C. for 1 h, there is prepared
2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-indol-1-yl)-amide (22%) as a solid. MS: 360 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.88 (s, 3H), 3.84 (s,
3H), 6.50 (d, H) 6.90 (m, H), 7.13 (d, H), 7.25-7.34 (m, 2H), 7.60
(m, H), 8.05 (m, H), 8.65 (d, H), 8.79 (d, H), 9.20 (s, 2H).
Example 141
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(1H-tetrazol-5-ylmethyl)-indol-1-yl]-amide
##STR00147##
[0930] Following procedures similar to those of Example 136, but
substituting 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid (3-cyanomethyl-indol-1-yl)-amide for
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(4-cyano-indol-1-yl)-amide, there is prepared
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(1H-tetrazol-5-ylmethyl)-indol-1-y]-amide (12%) as a solid. MS:
429 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.85 (s, 3H),
4.52 (s, 2H), 7.15 (m, H), 7.24-7.35 (m, 2H), 7.36-7.50 (m, 2H),
7.55 (m, H), 8.23 (d, H), 8.37 (d, H), 9.15 (s, H).
Example 142
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazinecarboxamide
##STR00148##
[0932] Following procedures similar to those of Example 64 but
substituting semicarbazide hydrochloride for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(2-phenyl-pyrimidine-5-carbonyl)-1-hydrozinecarboximide (62%) as
a solid. MS: 258 (M+H).
Example 143
2-(2-Phenyl-pyrimidine-5-carbonyl)-1-hydrazine-1-carbothioamide
##STR00149##
[0934] Following procedures similar to those of Example 64, but
substituting thiosemicarbazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
2-(2-phenyl-pyrimidine-5-carbonyl)-1-hydrozine-1-carbothioamide
(27%) as a solid. MS: 274 (M+H).
Example 144
2-Phenyl-pyrimidine-5-carboxylic acid
(2,4-dioxo-imidazolidin-1-yl)-amide
##STR00150##
[0936] Following procedures similar to those of Example 64 but
substituting 2,4-dioxo-imidazolidin-1-ylamine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid (2,4-dioxo-imidazolidin-1-yl)-amide (8%) as a solid. MS: 298
(M+H).
Example 145
2-Phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00151##
[0938] Following procedures similar to those of Example 64 but
substituting 6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-ylamine
for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic
acid methyl ester, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (39%) as
a solid. MS: 311 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
1.98 (s, 3H), 4.32 (s, 2H), 7.45-7.63 (m, 3H), 8.50 (d, 2H), 9.24
(s, 2H).
Example 146
2-Phenyl-pyrimidine-5-carboxylic acid N'-phenyl-hydrazide
##STR00152##
[0940] Following procedures similar to those of Example 64 but
substituting N'-phenyl-hydrazine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid N'-phenyl-hydrazide (18%) as a solid. MS: 291 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 6.34 (s, N--H), 6.82-7.04 (m,
2H), 7.15-7.39 (m, 3H), 7.40-7.63 (m, 3H), 7.94 (s, N--H), 8.51 (d,
2H), 9.20 (s, 2H).
Example 147
Pyridine-2-carboxylic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide
##STR00153##
[0942] Following procedures similar to those of Example 64, but
substituting 2-pyridine-2-carboxylic acid hydrazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared pyridine-2-carboxylic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide (52%) as a solid. MS:
320 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.75 (m,
4H), 7.98-8.14 (m, 2H), 8.46 (d, 2H), 8.73 (d, H), 9.32 (s, 2H),
10.81 (s, N--H), 10.96 (br, N--H).
Example 148
4-[N'-(2-Phenyl-pyrimidine-5-carbonyl)-hydrazino]-benzenesulfonamide
##STR00154##
[0944] Following procedures similar to those of Example 64, but
using substituting 4-hydrazino-benzebesulfonamide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared
4-[N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-benzenesulfonamide
(36%) as a solid. MS: 370 (M+H).
Example 149
3-Hydroxy-benzoic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide
##STR00155##
[0946] Following procedures similar to those of Example 64, but
substituting 3-hydroxy-benzoic acid hydrazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 3-hydroxy-benzoic acid
N'-(2-phenyl-pyrimidine-5-carbonyl)-hydrazide (56%) as a solid. MS:
335 (M+H).
Example 150
[0947] Benzo[1,3]dioxo-5-carboxylic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide
##STR00156##
[0948] Following procedures similar to those of Example 64, but
substituting benzo[1,3]dioxo-5-carboxylic acid hydrazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared benzo[1,3]-dioxo-5-carboxylic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide (83%) as a solid. MS:
363 (M+H).
Example 151
3,4-Dimethoxy-benzoic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide
##STR00157##
[0950] Following procedures similar to those of Example 64 but
substituting 3,4-dimethoxy-benzoic acid hydrazide for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 3,4-dimethoxy-benzoic acid
N'-(phenyl-pyrimidine-5-carbonyl)-hydrazide (76%) as a solid. MS:
379 (M+H).
Example 152
2-Phenyl-pyrimidine-5-carboxylic acid
N'-methyl-N'-phenyl-hydrazide
##STR00158##
[0952] Following procedures similar to those of Example 64, but
substituting N'-methyl-N'-phenyl-hydrazine for
3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid
methyl ester, there is prepared 2-phenyl-pyrimidine-5-carboxylic
acid N'-methyl-N'-phenyl-hydrazide (80 mg, 88%) as a solid. MS: 305
(M+H).
Example 153
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-indol-1-yl)-amide
##STR00159##
[0954] Step 1: A solution of potassium tert-butoxide (5.23 g, 46.62
mmol) and 5-methoxy-3-methylindole (3.41 g, 21.15 mmol) in DMF (20
mL) is stirred at rt for 45 min. A solution of monochloroamine in
ether (400 mL, 60 mmol) is added via an addition funnel over 15
min.
[0955] The resulting mixture is stirred for 2 h. The solvent is
removed and the residue is partitioned between EtOAc and water. The
organic phase is separated, washed with saturated aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue is purified by column
chromatography eluting with 10% EtOAc in heptane to afford
5-methoxy-3-methyl-indol-1-ylamine (1.42 g, 38%) as a solid. MS:
176 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.26-7.23 (m,
1H), 6.98-6.97 (m, 1H), 6.91-6.87 (m, 2H), 4.64 (br s, 2H), 3.86
(s, 3H), 2.26-2.25 (m, 3H).
[0956] Step 2: A microwave vial (20 mL) is charged with
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (657 mg,
2.83 mmol), HOTT (1.16 g, 3.11 mmol), DIPEA (1.35 mL, 7.73 mmol)
and DMF (6 mL). The mixture is stirred at 23.degree. C. under
N.sub.2 for 15 min. 5-Methoxy-3-methyl-indol-1-ylamine (456 mg,
2.59 mmol) is added and the vial is capped. The resulting mixture
is heated in a microwave (Biotage-Initiator) at 150.degree. C. for
6 min. The mixture is portioned between EtOAc and water. The
organic phase is separated, washed with saturated aqueous
NaHCO.sub.3, water and brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue is purified by column
chromatography eluting with 45% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-indol-1-yl)-amide (327 mg, 32%) as a solid. MS:
391 (M+H); .sup.1H NMR (300 MHz, d.sub.6-DMSO): .delta. 11.75 (s,
1H), 9.19 (s, 1H), 8.32 (d, 1H), 8.18-8.16 (m, 1H), 7.66-7.62 (m,
1H), 7.45 (td, 1H), 7.30 (d, 1H), 7.22 (s, 1H), 7.05 (d, 1H), 6.85
(dd, 1H), 3.81 (s, 3H), 2.76 (s, 3H), 2.27 (s, 3H).
Example 154
2-(3-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00160##
[0958] Step 1: Following the procedures similar to those of Example
59, step 1, but substituting 3-hydroxyphenylboronic acid for
3-methoxyphenylboronic acid, there is prepared
2-(3-hydroxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester.
[0959] Step 2: Following the procedures similar to those of Example
59, step 2, but substituting
2-(3-hydroxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester,
there is prepared 2-(3-hydroxy-phenyl)-pyrimidine-5-carboxylic
acid.
[0960] Step 3: Following the procedures similar to those of Example
59, step 3, but substituting
2-(3-hydroxy-phenyl)-pyrimidine-5-carboxylic acid for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid, there is
prepared 2-(3-hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide. MS: 327
(M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.91 (s, 3H), 4.22 (s,
2H), 5.75 (s, 1H), 6.98 (m, 1H), 7.36 (m, 1H), 7.90 (m, 1H), 9.25
(s, 2H), 9.71 (s, 1H), 9.95 (s, 1H), 11.05 (s, 1H). IC.sub.50=21
nM.
Example 155
2-(2-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00161##
[0962] Step 1: Following the procedures similar to those of Example
59, step 1, but substituting 2-hydroxyphenylboronic acid for
3-methoxyphenylboronic acid, there is prepared
2-(2-hydroxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester.
[0963] Step 2: Following the procedures similar to those of Example
59, step 2, but substituting
2-(2-hydroxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester,
there is prepared 2-(2-hydroxy-phenyl)-pyrimidine-5-carboxylic
acid.
[0964] Step 3: Following the procedures similar to those of Example
59, step 3, but substituting
2-(2-hydroxy-phenyl)-pyrimidine-5-carboxylic acid for
2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid, there is
prepared 2-(2-hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide. MS: 327
(M+H); H1 NMR (DMSO-d.sub.6): .delta.=1.91 (s, 3H), 4.22 (s, 2H),
7.02 (m, 2H), 7.50 (m, 1H), 8.46 (m, 1H), 9.32 (s, 2H), 9.97 (s,
1H), 11.12 (s, 1H), 12.95 (s, 1H).
Example 156
2-(4-Hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide
##STR00162##
[0966] A mixture of 2-(4-methoxy-phenyl)-pyrimidine-5-carboxylic
acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (100
mg, 0.29 mmol), sodium methanethiolate (206 mg, 2.9 mmol) and DMF
(2 mL) is stirred at 110.degree. C. for 6 h., and then cooled to
rt. The reaction mixture is concentrated in vacuo, and the residue
is purified on a reverse phase HPLC chromatography to afford
2-(4-hydroxy-phenyl)-pyrimidine-5-carboxylic acid
(6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (32 mg).
MS: 327 (M+H); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.87 (s, 3H),
4.17 (s, 2H), 6.74 (m, 2H), 8.21 (d, J=6.9 Hz, 2H), 9.08 (s, 2H),
9.53 (s, 1H).
Example 157
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00163##
[0968] Step 1: A flask containing 2-cyanopyrimidine (16.6 g, 158
mmol), ammonium acetate (14.6 g, 189.6 mmol) and N-acetylcysteine
(2.58 g, 15.8 mmol) and ethanol (160 mL) is heated to reflux. After
1.25 h, the reaction is allowed to cool slightly (to approximately
50.degree. C.), and sodium tert-butoxide (15.18 g, 158 mmol) and
ethanol (160 mL) are added. After stirring for 10 minutes,
2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (33.6 g,
181.7 mmol) is added. The reaction is then heated to reflux for an
additional 2 h. The reaction is then allowed to cool to rt, and
sodium hydroxide (12.6 g, 316 mmol) in water (50 mL) is added.
After 2 h, the reaction is chilled in an ice water bath and the
reaction pH is adjusted to 3 using a solution of 12M aqueous HCl.
The reaction mixture is then reduced in vacuo to 100 mL. Additional
water (100 mL) is added and the suspension is chilled in an ice
water bath, filtered and the solids are washed with minimal chilled
water. The solids are then dried in vacuo to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid (85%). MS: 217
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=2.80 (s, 3H),
7.66 (t, 1H), 9.01 (d, 2H), 9.14 (s, 1H).
[0969] Step 2. 4-Methyl-[2,2]bipyrimidinyl-5-carboxylic acid (0.5
g, 2.31 mmol) is combined with
5-fluoro-3-methyl-indol-1-yl-ammonium chloride (464 mg, 2.31 mmol),
N-methylmorpholine (233 mg, 2.31 mmol) and DMF (10 mL). The
suspension is stirred for 5 minutes at rt, then
4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium
chloride is added (640 mg, 2.31 mmol). The reaction is heated to
50.degree. C. for 4 h. The reaction is then poured into water (50
mL), the suspension is chilled for 2 h in the refrigerator, and
then filtered. The solids are then suspended in acetonitrile at
50.degree. C. for 4 h, cooled, then filtered to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (60%). MS: 363 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=2.27 (s, 3H), 2.77 (s, 3H), 7.07
(dt, 1H), 7.36 (dd, 1H), 7.38 (s, 1H), 7.44-7.48 (m, 1H), 7.70 (t,
1H), 9.05 (d, 2H), 9.29 (s, 1H), 11.9 (s, 1H). IC.sub.50=4.5
nM.
Example 158
2-Thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00164##
[0971] Step 1: A flask is charged with 2-cyanothiazole (6.7 g, 60.9
mmol), ammonium acetate (5.63 g, 73 mmol), N-acetylcysteine (993
mg, 6.09 mmol), and methanol (60 mL). The reaction is then heated
to reflux overnight. The reaction is reduced in vacuo to yield a
residue that is used in the next step without further
modifications.
[0972] Step 2: The crude residue from Step 1 is suspended in DMF
(100 mL). To this is added sodium
2-ethoxycarbonyl-3-oxo-but-1-en-1-olate (13.86 g, 70 mmol). The
reaction is then heated to 10.degree. C. for 1.5 h then allowed to
cool to rt. The reaction is then poured into ice water (1 L). The
suspension is filtered and the filtrate is successively extracted
with DCM (100 mL) and EtOAc (200 mL). The organic layers are dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a residue
(10.31 g).
[0973] Step 3: The residue from Step 2 (6.26 g, 28.32 mmol) is
combined with a solution of sodium hydroxide (2.26 g, 56.65 mmol)
in water (90 mL) and methanol (90 mL) and stirred at rt overnight.
The volume of solution is reduced by half under vacuo and the pH is
adjusted to 3 with aqueous HCl (approximately 12 M). The solid is
collected by filtration and dried in vacuo to afford
2-thiazol-2-yl-pyrimidine-5-carboxylic acid (56% over 3 steps). MS:
208 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=8.11 (d, 1H),
8.16 (d, 1H), 9.32 (s, 2H).
[0974] Step 4: A mixture of 2-thiazol-2-yl-pyrimidine-5-carboxylic
acid (50 mg, 0.244 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium
chloride (49 mg, 0.244 mmol), diisopropylethylamine (31.5 mg, 0.244
mmol) in DMF (1 mL) is stirred at rt for 5 min.
4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium
chloride (37 mg, 0.244 mmol) is added. The reaction is heated to
50.degree. C. for 1.5 h and then concentrated in vacuo. The residue
is taken up in DMSO-d.sup.6 then purified via reverse phase C18
HPLC chromatography eluting with water and acetonitrile containing
0.1% TFA buffer to afford 2-thiazol-2-yl-pyrimidine-5-carboxylic
acid (5-fluoro-3-methyl-indol-1-yl)-amide (58%). MS: 354 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=2.27 (s, 3H), 7.05 (dt,
1H), 7.32 (s, 1H), 7.32-7.44 (m, 2H), 8.11 (d, 1H), 8.19 (d, 1H),
9.42 (s, 2H), 12.12 (s, 1H).
Example 159
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00165##
[0976] Step 1: A solution of 2-cyanothiazole (1.55 g, 14.2 mmol) in
MeOH (12 mL) is treated with N-acetylcysteine (234 mg, 1.42 mmol),
ammonium acetate (1.5 g, 18.5 mmol) and heated in a microwave at
120.degree. C. for 15 min. The mixture is then treated with
2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (3.2 g,
17.0 mmol) and KOt-Bu (2.2 g, 20 mmol), and heated in a microwave
at 120.degree. C. for an additional 15 min. The mixture is then
treated with a solution of KOH (1.2 g, 20 mmol) in H.sub.2O (5 mL)
and heated at reflux for 1 h. The mixture is neutralized with
concentrated aqueous HCl. The precipitate is collected by
filtration and dried to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (1.95 g, 62%).
MS: 222 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 13.77
(s. OH, 1H), 9.18 (s, 1H), 8.13 (d, 1H), 8.07 (d, 1H), 2.81 (s,
3H).
[0977] Step 2: A mixture of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (221 mg, 1
mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (200 mg, 1
mmol) and N-methylmorpholine (101 mg, 1 mmol) in DMF (5 mL) is
stirred at rt for 5 min.
4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium
chloride (277 mg, 1 mmol) is added and the reaction is heated to
50.degree. C. for 4 h. The reaction mixture is then poured into
water (50 mL). The precipitate is collected via filtration and
dried in vacuo to provide
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (68%). MS: 368 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=2.27 (s, 3H), 2.76 (s, 3H), 7.06
(dt, 1H), 7.35-7.38 (m, 2H), 7.42-7.47 (m, 1H), 8.07 (d, 1H), 8.14
(d, 1H), 9.22 (s, 1H), 11.9 (s, 1H).
Example 160
[2,2']Bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00166##
[0979] Step 1: A pressure vessel is charged with 2-cyanopyrimidine
(7.88 g, 75 mmol), N-acetyl cysteine (1.22 g, 7.5 mmol), ammonium
acetate (6.93 g, 90 mmol), and MeOH (75 mL). The vessel is sealed
and heated at 110.degree. C. for 1.5 h, and then cooled to rt. To
the reaction mixture is added sodium
2-ethoxycarbonyl-3-oxo-but-1-en-1-olate (17 g, 86.25 mmol) and MeOH
(75 mL). The mixture is heated to reflux for 1.5 h and then cooled
to rt. NaOH (6 g, 150 mmol) and water (80 mL) are added. The
mixture is stirred for 30 min or until LC-MS indicates complete
hydrolysis of the intermediate ester. The pH of the reaction
mixture is adjusted to 3 with concentrated (12 M) aqueous HCl. MeOH
is evaporated in vacuo, and the resulting precipitate is collected
via filtration and washed with minimal chilled water to yield
[2,2']bipyrimidinyl-5-carboxylic acid (59%). MS: 203 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=7.71 (t, 1H), 9.06 (d, 2H), 9.40
(s, 2H).
[0980] Step 2: A mixture of [2,2']bipyrimidinyl-5-carboxylic acid
(166 mg, 0.82 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride
(164 mg, 0.82 mmol) and DIPEA (106 mg, 0.82 mmol) in DMF (5 mL) is
stirred at rt for 5 min.
4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium
chloride (226 mg, 0.82 mmol) is added. The reaction mixture is
heated to 50.degree. C. for 1.5 h and then concentrated in vacuo.
The residue is taken up in DMSO-d.sup.6 and then purified via
reverse phase C18 HPLC chromatography eluting with water and
acetonitrile containing 0.1% TFA buffer to afford
[2,2]bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (56%). MS: 349 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta.=2.27 (s, 3H), 7.05 (dt, 1H),
7.33 (s, 1H), 7.36 (dd, 1H), 7.42-7.46 (m, 1H), 7.72 (t, 1H), 9.07
(d, 2H), 9.51 (s, 2H), 12.17 (s, 1H).
Example 161
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylicacid(3
chloro-5-fluoro-indol-1-yl)-amide
##STR00167##
[0982] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (300 mg, 0.824 mmol) in MeCN (20 mL) is
treated with NCS (185 mg, 1.42 mmol) and the mixture is stirred at
60.degree. C. in a sealed flask for 2 h. The mixture is then
concentrated, diluted with 10% aqueous Na.sub.2S.sub.2O.sub.8 (20
mL), and extracted with EtOAc (3.times.20 mL). The combined organic
layer is separated, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 10%-20% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylicacid(3
chloro-5-fluoro-indol-1-yl)-amide (160 mg, 49%). MS: 399 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.79 (s, 1H), 8.04 (d,
1H), 7.92 (d, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.00 (m, 3), 6.76
(m, 1), 2.52 (s, 3H).
Example 162
5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-
-indole-3-carboxylic acid amide
##STR00168##
[0984] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in 2-Me-THF (7 mL)
is treated with chlorosulfonyl isocyanate (CSI) (85 uL, 2.0 mmol)
at 0.degree. C., and the mixture is warmed to rt for 2 h. The
mixture is then cooled to 0.degree. C., treated with 1 M NaOH (1
mL), diluted with brine (20 mL), and extracted with EtOAc
(3.times.20 mL). The combined organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1-
H-indole-3-carboxylic acid amide (275 mg, 83%). MS: 408 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.27 (s, 1H), 8.35 (d,
1H), 8.26 (s, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.59 (m, 3H), 7.15
(m, 1H), 2.78 (s, 3H). IC.sub.50=8 nM.
Example 163
2-{1,5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-
-indol-3-yl}-2-methyl-propionic acid
##STR00169##
[0986] Step 1: A solution of (5-fluoro-1H-indol-3-yl)-acetic acid
methyl ester (3 g, 14.8 mmol) in MeCN (25 mL) is treated with
Boc.sub.2O (4.3 g, 16.3 mmol) and DMAP (200 mg, 1.63 mmol), and the
mixture is stirred at rt for 1 h. The mixture is diluted with
saturated aqueous NH.sub.4Cl (50 mL), and extracted with DCM
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 8% EtOAc in
heptane to afford
5-fluoro-3-methoxycarbonylmethyl-indole-1-carboxylic acid
tert-butyl ester (1.6 g, 35%). MS: 371 (M+Na.sup.+ ACN); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 8.09 (m, 1H), 7.59 (s, 1H), 7.17
(m, 1H), 7.04 (m, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 1.55 (s,
9H).
[0987] Step 2: A solution of
5-fluoro-3-methoxycarbonylmethyl-indole-1-carboxylic acid
tert-butyl ester (1.6 g, 5.2 mmol) in 2-Me-THF (50 mL) at
-78.degree. C. is treated with LDA (5.7 mL 1.8 M in THF, 10.4 mmol)
and stirred for 0.5 h. MeI (1.02 mL, 15.6 mmol) is added and the
mixture is warmed to 0.degree. C. over 2 h. The mixture is diluted
with saturated aqueous NH.sub.4Cl (50 mL), and extracted with EtOAc
(3.times.50 mL). The combined organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
5-fluoro-3-(1-methoxycarbonyl-1-methyl-ethyl)-indole-1-carboxylic
acid tert-butyl ester, which is used in the next step without
further purification.
[0988] Step 3: A solution of
5-fluoro-3-(1-methoxycarbonyl-1-methyl-ethyl)-indole-1-carboxylic
acid tert-butyl ester (5.2 mmol) in MeOH (25 mL) is treated with
K.sub.2CO.sub.3 (720 mg, 5.2 mmol) and heated at reflux for 2 h.
The mixture is diluted with brine (50 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
2-(5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester
(650 mg, 53%, 2 steps), which is used in the next step without
further purification. MS: 236 (M+H); .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 7.35 (m, 1H), 7.30 (m, 1H), 7.14 (m, 1H),
6.91 (m, 1H), 3.54 (s, 3H), 1.57 (s, 6H).
[0989] Step 4: A suspension of NaH (1.02 g, 25.5 mmol, 60% in
mineral oil) in DMF (25 mL) at 0.degree. C. is treated with
2-(5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester
(400 mg, 1.7 mmol) and stirred at 0.degree. C. for 0.5 h. The
mixture is treated with HOSA (960 mg, 8.5 mmol) portion wise and
warmed to rt over 2 h. The mixture is then poured over ice,
filtered through a pad of Celite, and extracted with EtOAc
(3.times.100 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl
ester, which is used in the next step without further
purification.
[0990] Step 5: A solution of
2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl
ester (0.85 mmol) and
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (201 mg, 0.935
mmol) in DMF (8.5 mL) is stirred at 40.degree. C. for 0.5 h. The
mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at
60.degree. C. for 1 h. The mixture is concentrated in vacuo,
diluted with saturated aqueous Na.sub.2CO.sub.3 (20 mL), and
extracted with EtOAc (3.times.20 mL). The combined organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
afford
2-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl}-2-methyl-propionic acid methyl ester, which is used in
the next step without further purification.
[0991] Step 6: A solution of
2-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl}-2-methyl-propionic acid methyl ester (0.85 mmol) in
MeOH (5 mL) is treated with 10% aqueous NaOH (2 mL) and stirred at
rt overnight. The mixture is then concentrated, diluted with EtOAc
(50 mL), and extracted with 10% aqueous NaOH (3.times.50 mL). The
aqueous layer is acidified with 12 M aqueous HCl, extracted with
DCM (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
triturated with Et.sub.2O to afford
2-[5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl]-2-methyl-propionic acid (100 mg, 27%, 3 steps). MS: 434
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.26 (s, 1H),
8.79 (m, 1H), 8.44 (d, 1H), 8.03 (t, 1H), 7.59 (m, 1H), 7.53 (s,
1H), 7.49 (m, 1H), 7.35 (d, 1H), 7.08 (t, 1H), 2.79 (s, 3H), 1.59
(s, 6H).
Example 164
2-(5-Fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-
-1H-indol-3-yl)-2-methyl-propionic acid
##STR00170##
[0993] Step 1: A solution of
2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl
ester (0.85 mmol) and
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (217 mg,
0.935 mmol) in DMF (8.5 mL) is stirred at 40.degree. C. for 0.5 h.
The mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred
at 60.degree. C. for 1 h. The mixture is concentrated in vacuo,
diluted with saturated aqueous Na.sub.2CO.sub.3 (20 mL), and
extracted with EtOAc (3.times.20 mL). The combined organic layer is
separated, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo to afford
2-(5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino-
}-1H-indol-3-yl)-2-methyl-propionic acid methyl ester, which is
used in the next step without further purification.
[0994] Step 2: A solution of
2-(5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino-
}-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (0.85 mmol)
in MeOH (5 mL) is treated with 10% aqueous NaOH (2 mL) and stirred
at rt overnight. The mixture is then concentrated, diluted with
EtOAc (50 mL), and extracted with 10% aqueous NaOH (3.times.50 mL).
The aqueous layer is acidified with 12 M HCl, and extracted with
DCM (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
triturated with Et.sub.2O to afford
2-(5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl-amino}-
-1H-indol-3-yl)-2-methyl-propionic acid (139 mg). MS: 451 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.22 (s, 1H), 8.33 (d,
1H), 8.18 (d, 1H), 7.63 (m, 1H), 7.50 (m, 3H), 7.33 (m, 1H), 7.07
(m, 1H), 2.78 (s, 3H), 1.59 (s, 6H). IC.sub.50=7 nM.
Example 165
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide
##STR00171##
[0996] Step 1: A solution of 5-fluoroindole (10.5 g, 78 mmol) in
MeCN (150 mL) at 0.degree. C. is treated with methyl vinyl ketone
(9.5 mL, 117 mmol) and Sc(OTf).sub.3 (383 mg, 0.78 mmol) and
stirred for 1 h. The mixture is then stirred an additional 6 h at
rt. The mixture is concentrated in vacuo. The residue is purified
by silica gel chromatography eluting with 10%-50% EtOAc in heptane
to afford 4-(5-fluoro-1H-indol-3-yl)-butan-2-one (11.1 g, 70%).
[0997] Step 2: A solution of 4-(5-fluoro-1H-indol-3-yl)-butan-2-one
(11.1 g, 54.1 mmol) in THF (200 mL) at 0.degree. C. is treated with
MeMgBr (54.1 mL, 3 M in THF, 162.3 mmol) and stirred at 0.degree.
C. for 2 h, and warmed to rt overnight. The mixture is then poured
over ice, treated with solid NH.sub.4Cl (3 g), and extracted with
EtOAc (3.times.120 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 10%-60% EtOAc
in heptane to afford 4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol
(3.07 g, 26%). MS: 222 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.94 (s, NH, 1H), 7.22 (m, 2H), 7.03 (s, 1H), 6.93 (m, 1H),
2.81 (m, 2H), 1.90 (m, 2H), 1.33 (s, 6H).
[0998] Step 3: A suspension of NaH (8.1 g, 204 mmol, 60% in mineral
oil) in DMF (100 mL) at 0.degree. C. is treated with
4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (3 g, 13.6 mmol) and
stirred at 0.degree. C. for 0.5 h. The mixture is treated with HOSA
(7.7 g, 68 mmol) portion wise and warmed to rt over 2 h. The
mixture is then poured over ice, filtered through a pad of Celite,
and extracted with EtOAc (3.times.100 mL). The combined organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue is purified by filtration through a short plug
of silica gel to afford
4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol, which is
used in the next step without further purification. MS: 237 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.30 (m, 1H), 7.22 (m,
1H), 6.98 (m, 2H), 4.71 (s, NH.sub.2, 2H), 2.75 (m, 2H), 1.86 (m,
2H), 1.31 (s, 6H).
[0999] Step 4: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg,
1.2 mmol) and
4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (1.2 mmol)
in DMF (10 mL) is stirred at 50.degree. C. for 1 h. The mixture is
treated with DMTMM (331 mg, 1.2 mmol) and stirred at 50.degree. C.
for 1 h. The mixture is concentrated in vacuo, diluted with
saturated aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with
EtOAc (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 50% EtOAc in
heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (330 mg,
61%). MS: 451 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
9.10 (s, 1H), 8.36 (d, 1H), 8.23 (d, 1H), 7.55 (m, 1H), 7.32 (m,
3H), 7.18 (s, 1H), 7.03 (m, 1H), 3.91 (s, OH, 1H), 2.84 (s, 3H),
2.82 (m, 2H), 1.91 (m, 2H), 1.31 (s, 6H).
Example 166
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide
##STR00172##
[1001] A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic
acid (516 mg, 4 mmol) and
4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (566 mg, 4
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (662 mg, 4 mmol) and stirred at
50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 4%-10% MeOH
in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic
acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (450
mg, 44%). MS: 434 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.25 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.02 (m, 1H),
7.58 (m, 1H), 7.43 (m, 3H), 7.06 (m, 1H), 4.29 (s, OH, 1H), 2.78
(s, 3H), 2.72 (m, 2H), 1.77 (m, 2H), 120 (s, 6H).
Example 167
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-yl]-amide
##STR00173##
[1003] Step 1: A solution of 5-fluorogramine (576 mg, 3 mmol) and
pyridine-3-carboxaldehyde (531 mg, 3 mmol) in MeCN (6 mL) is
treated with Bu.sub.3P (1.12 mL, 4.5 mmol) and stirred at
90.degree. C. for 24 h. The mixture is concentrated, filtered
through a pad of silica gel eluting with 30% EtOAc in heptane to
afford 5-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indole as a mixture of
olefin isomers, which is used in the next step without further
purification.
[1004] Step 2: A solution of
5-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indole (3 mmol) in MeOH (10
mL) is treated with Pd/C (200 mg) and shaken in a Parr apparatus
under 40 atm of H.sub.2 for 18 h. The mixture is filtered through
Celite and the filtrate is concentrated in vacuo. The residue is
purified by silica gel chromatography eluting with 0%-10% MeOH in
DCM to afford 5-fluoro-3-(2-pyridin-3-yl-ethyl)-1H-indole (360 mg,
50%, 2 steps).
[1005] Step 3: A suspension of NaH (600 mg, 15 mmol, 60% in mineral
oil) in DMF (10 mL) at 0.degree. C. is treated with
5-fluoro-3-(2-pyridin-3-yl-ethyl)-1H-indole (240 mg, 1 mmol) and
stirred at 0.degree. C. for 0.5 h. The mixture is treated with HOSA
(565 mg, 5 mmol) portion wise and warmed to rt over 2 h. The
mixture is then poured over ice, filtered through a pad of Celite,
and extracted with EtOAc (3.times.1050 mL). The combined organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo to afford 5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-ylamine,
which is used in the next step without further purification.
[1006] Step 4: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (232 mg,
1 mmol) and 5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-ylamine (255
mmol) in DMF (10 mL) is stirred at 50.degree. C. for 10 min. The
mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 0.5 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by triturating in MeOH:H.sub.2O (2:1) to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(2-pyridin-3-yl-ethyl)-indol-1-yl]-amide (6 mg, 1%).
MS: 470 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.21
(s, 1H), 8.51 (m, 1H), 8.40 (m, 1H), 8.33 (d, 1H), 8.19 (d, 1H),
7.74 (d, 1H), 7.63 (m, 1H), 7.45 (m, 4H), 7.33 (m, 1H), 7.06 (m,
1H), 3.29 (s, 2H), 3.01 (s, 2H), 2.77 (s, 3H).
Example 168
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-formyl-indol-1-yl)-amide
##STR00174##
[1008] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-indol-1-yl)-amide (250 mg, 0.55 mmol) in H.sub.2O (5.5
mL) is treated with DDQ (369 mg, 1.6 mmol) in EtOAc (0.5 mL), and
stirred at rt for 2 h. The mixture is diluted with EtOAc (50 mL),
washed with brine (50 mL), and extracted with saturated aqueous
NaHCO.sub.3 (3.times.50 mL). The aqueous layer is acidified to pH 2
with HCl (conc.) and washed with Et.sub.2O (50 mL). The aqueous
layer is neutralized with 10% aqueous NaOH and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by triturating in Et.sub.2O to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-formyl-indol-1-yl)-amide (87 mg, 43%). MS: 376 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.53 (s, NH, 1H),
10.00 (s, 1H), 9.34 (m, 1H), 8.81 (m, 1H), 8.66 (s, 1H), 8.48 (m,
1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 7.27
(m, 1H), 2.80 (s, 3H).
Example 169
5-Fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indo-
le-3-carboxylic acid
##STR00175##
[1010] Step 1: A solution of 5-fluoro-1H-indole-3-carboxylic acid
methyl ester (510 mg, 2.6 mmol) in NMP (6.5 mL) at rt is treated
with KOt-Bu (342 mg, 2.9 mmol) and stirred at rt for 0.5 h.
[1011] A solution of O-amino-4-nitrobenzoic acid (558 mg, 3.0 mmol)
in NMP (2.5 mL) is added and the mixture is stirred for 3 h. The
mixture is diluted with EtOAc (50 mL) and washed with 10% aqueous
NaHCO.sub.3 (50 mL). The organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
1-amino-5-fluoro-1H-indole-3-carboxylic acid methyl ester, which is
used in the next step without further purification.
[1012] Step 2: A solution of
2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (559 mg, 2.6
mmol) and 1-amino-5-fluoro-1H-indole-3-carboxylic acid methyl ester
(540 mg, 2.6 mmol) in DMF (25 mL) is stirred at 50.degree. C. for
0.5 h. The mixture is treated with DMTMM (718 mg, 2.6 mmol) and
stirred at 50.degree. C. for 1 h. The mixture is diluted with
saturated aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with
EtOAc (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 1%-10% MeOH
in DCM to afford
5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-ind-
ole-3-carboxylic acid methyl ester.
[1013] Step 3: A solution of
5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-ind-
ole-3-carboxylic acid methyl ester (2.6 mmol) in MeOH (10 mL) is
treated with an aqueous solution of KOH (500 mg, 8.9 mmol) in
H.sub.2O (200 mL) and heated at reflux for 2 h. The mixture is
diluted with EtOAc (50 mL) and extracted with 1% aqueous KOH
(3.times.50 mL). The combined aqueous layer is neutralized with HCl
(conc.), and the precipitate is collected by filtration and dried
in vacuo to afford
5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-ind-
ole-3-carboxylic acid (195 mg, 19%, 3 steps). MS: 392 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.44 (s, OH, 1H),
12.31 (s, NH, 1H), 9.31 (s, 1H), 8.81 (d, 1H), 8.48 (d, 1H), 8.35
(s, 1H), 8.03 (m, 1H), 7.77 (m, 1H), 7.62 (m, 2H), 7.19 (m, 1H),
2.79 (s, 3H).
Example 170
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-hydroxymethyl-indol-1-yl)-amide
##STR00176##
[1015] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-formyl-indol-1-yl)-amide (230 mg, 0.614 mmol) in MeOH
(10 mL) is treated with NaBH.sub.4 (233 mg, 6.14 mmol) and stirred
at rt for 1 h. The mixture is diluted with EtOAc (50 mL) and
H.sub.2O, neutralized with HCl (conc.), and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by preparative reverse-phase HPLC eluting with 20%-100%
MeCN in H.sub.2O to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-hydroxymethyl-indol-1-yl)-amide (90 mg, 8%). MS: 378
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.92 (s, NH,
1H), 9.27 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.05 (m, 1H), 7.61
(m, 1H), 7.44 (m, 3H), 7.10 (m, 1H), 5.00 (t, OH, 1H), 4.66 (d,
2H), 2.78 (s, 3H).
Example 171
4-Methyl-[2,2]bipyrimidinyl-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide
##STR00177##
[1017] A solution of 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(300 mg, 1.38 mmol) and
4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (325 mg,
1.38 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (380 mg, 1.38 mmol) and stirred at
50.degree. C. for 2 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0%-7% MeOH in
DCM to afford 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (200 mg,
33%). MS: 435 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
9.26 (s, 1H), 9.09 (d, 2H), 7.70 (t, 1H), 7.29 (m, 2H), 7.22 (s,
1H), 7.01 (m, 1H), 2.90 (s, 3H), 2.82 (m, 2H), 1.91 (m, 2H), 1.31
(s, 6H).
Example 172
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide
##STR00178##
[1019] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (300 mg, 1.36
mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol
(325 mg, 1.38 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1
h. The mixture is treated with DMTMM (380 mg, 1.38 mmol) and
stirred at 50.degree. C. for 2 h. The mixture is diluted with
saturated aqueous Na.sub.2CO.sub.3 (50 mL), and extracted with
EtOAc (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0%-7% MeOH in
DCM to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (155 mg,
26%). MS: 440 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
9.22 (s, 1H), 8.14 (d, 1H), 8.08 (d, 1H), 7.40 (m, 3H), 7.06 (m,
1H), 4.31 (s, OH, 1H), 2.76 (s, 3H), 2.71 (m, 2H), 1.77 (m, 2H),
1.20 (s, 6H). IC.sub.50=5 nM.
Example 173
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide
##STR00179##
[1021] Step 1: A solution of 2-iodo-4-trifluoromethyl-phenylamine
(10 g, 34.8 mmol) in DCM (100 mL) is treated with TFAA (5.55 mL,
41.8 mmol) and pyridine (3.4 mL, 41.8 mmol), and stirred at rt for
1 h. The mixture is diluted with H.sub.2O (150 mL), and extracted
with DCM (3.times.150 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is diluted with MeCN (100 mL), treated with trans-crotyl bromide
(5.4 mL, 52.2 mmol) and K.sub.2CO.sub.3 (9.6 g, 69.6 mmol), and
heated at reflux for 2 h. The mixture is cooled, filtered through a
pad of Celite and concentrated. The residue is purified by silica
gel chromatography eluting with 0%-10% EtOAc in heptane to afford
N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-4-trifluoromethyl-phenyl)-acetamid-
e (12.7 g, 84%). MS: 438 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 8.18 (s, 1H), 7.67 (s, 1H), 7.26 (m, 1H), 5.52 (m, 2H),
4.88 (m, 1H), 3.51 (m, 1H), 1.68 (d, 3H).
[1022] Step 2: A solution of
N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-4-trifluoromethyl-phenyl)-acetamid-
e (12.7 g, 29 mmol) in DMF (60 mL) is treated with n-Bu.sub.4NCl
(8.8 g, 32 mmol), Pd(OAc).sub.2 (131 mg, 0.58 mmol), and stirred at
100.degree. C. for 2 h. The mixture is cooled to rt, diluted with
EtOAc (150 mL), filtered through a pad of silica gel, and washed
with 1 M HCl (150 mL). The organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 10%-30% EtOAc
in heptane to afford 3-ethyl-5-trifluoromethyl-1H-indole (2.6 g,
42%). MS: 214 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.08 (s, NH, 1H), 7.89 (s, 1H), 7.41 (m, 2H), 7.07 (m, 1H), 2.81
(q, 2H), 1.34 (t, 3H).
[1023] Step 3: A suspension of NaH (7 g, 176 mmol, 60% in mineral
oil) in DMF (50 mL) at 0.degree. C. is treated with
3-ethyl-5-trifluoromethyl-1H-indole (2.4 g, 11.3 mmol) and stirred
at 0.degree. C. for 1 h. The mixture is treated with HOSA (6.6 g,
59 mmol) portion wise and warmed to rt over 2 h. The mixture is
then poured over ice, filtered through a pad of Celite, and
extracted with EtOAc (3.times.150 mL). The combined organic layer
is dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
The residue is purified by silica gel chromatography eluting with
10%-50% EtOAc in heptane to afford
3-ethyl-5-trifluoromethyl-indol-1-ylamine (1.3 g, 50%). MS: 229
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.84 (s, 1H),
7.45 (s, 2H), 7.02 (s, 1H), 4.74 (s, NH.sub.2, 2H), 2.77 (q, 2H),
1.31 (t, 3H).
[1024] Step 4: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (232 mg,
1.0 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228 mg, 1
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 2 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (240 mg, 54%). MS: 443
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.24 (s, 1H),
8.34 (d, 1H), 8.26 (d, 1H), 8.19 (s, 1H), 7.58 (m, 2H), 7.42 (m,
3H), 2.84 (q, 2H), 2.78 (s, 3H), 1.31 (t, 3H).
Example 174
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide
##STR00180##
[1026] A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic
acid (215 mg, 1 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine
(228 mg, 1 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h.
The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 2 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (235 mg, 55%). MS: 426
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.28 (s, 1H),
8.81 (d, 1H), 8.48 (d, 1H), 8.03 (m, 1H), 7.99 (s, 1H), 7.60 (m,
4H), 2.82 (q, 2H), 2.79 (s, 3H), 1.31 (t, 3H).
Example 175
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide
##STR00181##
[1028] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (221 mg, 1
mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228 mg, 1
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 2 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (250 mg, 58%). MS: 432
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.07 (s, NH,
1H), 9.25 (s, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.99 (s, 1H), 7.68
(d, 1H), 7.51 (m, 2H), 2.77 (s, 3H), 2.74 (q, 2H), 1.29 (t,
3H).
Example 176
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide
##STR00182##
[1030] A solution of 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(216 mg, 1 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228
mg, 1 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 2 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo. The
solid is triturated in Et.sub.2O to afford
4-methyl-[22']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (100 mg, 23%). MS: 427
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.11 (s, NH,
1H), 9.32 (s, 1H), 9.07 (d, 2H), 8.00 (s, 1H), 7.69 (m, 2H), 7.53
(m, 2H), 2.80 (q, 2H), 2.79 (s, 3H), 1.31 (t, 3H). IC.sub.50=8
nM.
Example 177
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide
##STR00183##
[1032] Step 1: A solution of 2-bromo-4-trifluoromethoxy-phenylamine
(7.6 g, 29.7 mmol) in DCM (60 mL) is treated with TFAA (5 mL, 35.6
mmol) and pyridine (2.87 mL, 35.6 mmol), and stirred at rt
overnight. The mixture is diluted with H.sub.2O (150 mL), and
extracted with DCM (3.times.150 mL). The combined organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residue is diluted with MeCN (60 mL), treated with trans-crotyl
bromide (4.6 mL, 44.5 mmol) and K.sub.2CO.sub.3 (8.1 g, 59 mmol),
heated at reflux for 1 h, and then stirred at rt for 2 h. The
mixture is filtered through a pad of Celite and the filtrate is
concentrated. The residue is purified by silica gel chromatography
eluting with 0%-15% EtOAc in heptane to afford
N-(2-bromo-4-trifluoromethoxy-phenyl)-N-but-2-enyl-2,2,2-trifluoro-acetam-
ide (10.5 g, 87%). MS: 406 (M+); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.56 (s, 1H), 7.22 (m, 2H), 5.52 (m, 2H), 4.86 (m, 1H),
3.57 (m, 1H), 1.65 (d, 3H).
[1033] Step 2: A solution of
N-(2-bromo-4-trifluoromethoxy-phenyl)-N-but-2-enyl-2,2,2-trifluoro-acetam-
ide (10 g, 24.7 mmol) in DMF (50 mL) is treated with n-Bu.sub.4NCl
(7.5 g, 27.2 mmol), Pd(OAc).sub.2 (221 mg, 0.98 mmol), and stirred
at 100.degree. C. for 1 h. H.sub.2O (10 mL) is added, and the
mixture is cooled to rt, filtered through a pad of silica gel. The
filtrate is extracted with heptane (3.times.50 mL). The combined
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 0%-25% EtOAc in heptane to afford
3-ethyl-5-trifluoromethoxy-1H-indole (3.1 g, 55%). MS: 230 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.97 (s, NH, 1H), 7.44
(s, 1H), 7.29 (m, 1H), 7.07 (m, 2H), 2.77 (q, 2H), 1.32 (t,
3H).
[1034] Step 3: A suspension of NaH (7.9 g, 197 mmol, 60% in mineral
oil) in DMF (60 mL) at 0.degree. C. is treated with
3-ethyl-5-trifluoromethoxy-1H-indole (3 g, 13.1 mmol) and stirred
at 0.degree. C. for 1 h. The mixture is treated with HOSA (7.4 g,
65.5 mmol) portion wise and warmed to rt over 2 h. The mixture is
then poured over ice and filtered through a pad of Celite. The
filtrate is extracted with heptane (3.times.50 mL). The combined
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 10%-30% EtOAc in heptane to afford
3-ethyl-5-trifluoromethoxy-indol-1-ylamine (2.05 g, 64%). MS: 245
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.37 (m, 2H),
7.11 (m, 1H), 7.00 (s, 1H), 4.72 (s, NH.sub.2, 2H), 2.73 (q, 2H),
1.29 (t, 3H).
[1035] Step 4: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (250 mg,
1.1 mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at
50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min. The
precipitate is collected by filtration, washed with H.sub.2O (50
mL) and heptane (50 mL), and dried in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (270 mg, 59%). MS:
459 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 11.51 (s, NH,
1H), 9.08 (s, 1H), 8.35 (d, 1H), 8.24 (d, 1H), 7.48 (m, 2H), 7.22
(m, 2H), 7.11 (m, 2H), 2.85 (s, 3H), 2.80 (q, 2H), 1.35 (t,
3H).
Example 178
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide
##STR00184##
[1037] A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic
acid (250 mg, 1.1 mmol) and
3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1.0 mmol) in
DMF (5 mL) is stirred at 50.degree. C. for 1 h. The mixture is
treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50.degree. C.
for 1 h. The mixture is diluted with saturated aqueous
Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min. The precipitate is
collected by filtration, washed with H.sub.2O (50 mL) and heptane
(50 mL), and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (300 mg, 68%). MS:
442 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.27 (s,
1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.03 (m, 1H), 7.57 (m, 3H), 7.47
(s, 1H), 7.21 (d, 1H), 2.78 (s, 3H), 2.74 (q, 2H), 1.29 (t,
3H).
Example 179
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide
##STR00185##
[1039] A solution of 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(250 mg, 1.1 mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine
(244 mg, 1 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h.
The mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at
50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min. The
precipitate is collected by filtration, washed with H.sub.2O (50
mL) and heptane (50 mL), and dried in vacuo to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (130 mg, 29%). MS:
443 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.25 (s,
1H), 9.05 (d, 2H), 7.69 (t, 1H), 7.64 (s, 1H), 7.54 (m, 2H), 7.14
(d, 1H), 2.80 (s, 3H), 2.76 (q, 2H), 1.29 (t, 3H).
Example 180
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide
##STR00186##
[1041] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (250 mg, 1.1
mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1.0
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at
50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min.
[1042] The precipitate is collected by filtration, washed with
H.sub.2O (50 mL) and heptane (50 mL), and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (250 mg, 56%). MS:
448 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.23 (s,
1H), 8.15 (m, 1H), 8.09 (m, 1H), 7.55 (m, 2H), 7.48 (s, 1H), 7.19
(d, 1H), 2.78 (s, 3H), 2.71 (m, 2H), 1.29 (t, 3H).
Example 181
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide
##STR00187##
[1044] Step 1: A suspension of NaH (6.5 g, 162 mmol, 60% in mineral
oil) in DMF (54 mL) at 0.degree. C. is treated with
6-trifluoromethylindole (2.0 g, 10.8 mmol) and stirred at 0.degree.
C. for 0.5 h. The mixture is treated with HOSA (6.1 g, 54 mmol)
portion wise and warmed to rt over 2 h. The mixture is then poured
over ice and filtered through a pad of Celite. The filtrate is
extracted with Et.sub.2O (3.times.50 mL). The combined organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 10%-30% EtOAc in heptane to afford
6-trifluoromethyl-indol-1-ylamine (1.79 g, 83%). MS: 201 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.74 (s, 1H), 7.67 (d,
1H), 7.35 (d, 1H), 7.30 (m, 1H), 6.45 (d, 1H), 4.83 (s, NH.sub.2,
2H).
[1045] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg,
1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1 mmol) in
DMF (5 mL) is stirred at 50.degree. C. for 0.5 h. The mixture is
treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50.degree. C.
for 1 h. The mixture is diluted with saturated aqueous
Na.sub.2CO.sub.3 (5 mL) and extracted with EtOAc (3.times.50 mL).
The combined organic layer is dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The residue is triturated with
Et.sub.2O/heptane overnight. The precipitate is collected by
filtration, washed with H.sub.2O (50 mL) and heptane (50 mL), and
dried in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide (180 mg, 44%). MS: 415 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.09 (s, NH, 1H),
9.33 (s, 1H), 8.35 (d, 1H), 8.20 (d, 1H), 7.90 (s, 1H), 7.79 (m,
2H), 7.65 (m, 1H), 7.46 (m, 2H), 6.74 (d, 1H), 2.79 (s, 3H).
Example 182
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide
##STR00188##
[1047] A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic
acid (258 mg, 1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200
mg, 1 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 0.5 h.
The mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred
at 50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is triturated with Et.sub.2O/heptane overnight. The precipitate is
collected by filtration, washed with H.sub.2O (50 mL) and heptane
(50 mL), and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide (160 mg, 40%). MS: 398 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.13 (s, NH, 1H),
9.36 (s, 1H), 8.82 (d, 1H), 8.48 (d, 1H), 8.04 (m, 1H), 7.83 (m,
3H), 7.60 (m, 1H), 7.44 (d, 1H), 6.74 (d, 1H), 2.80 (s, 3H).
Example 183
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide
##STR00189##
[1049] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (265 mg, 1.2
mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1 mmol) in DMF
(5 mL) is stirred at 50.degree. C. for 0.5 h. The mixture is
treated with DMTMM (290 mg, 1.05 mmol) and stirred at 50.degree. C.
for 1 h.
[1050] The mixture is diluted with saturated aqueous
Na.sub.2CO.sub.3 (5 mL) and extracted with EtOAc (3.times.50 mL).
The combined organic layer is dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo.
[1051] The residue is triturated with Et.sub.2O/heptane overnight.
The precipitate is collected by filtration, washed with H.sub.2O
(50 mL) and heptane (50 mL), and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide (160 mg, 40%). MS: 404 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.12 (s, NH, 1H),
9.33 (s, 1H), 8.15 (d, 1H), 8.05 (d, 1H), 7.91 (s, 1H), 7.79 (m,
2H), 7.44 (m, 1H), 6.73 (d, 1H), 2.77 (s, 3H).
Example 184
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide
##STR00190##
[1053] A solution of 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(259 mg, 1.2 mmol) and 6-trifluoromethyl-indol-1-ylamine (200 mg, 1
mmol) in DMF (5 mL) is stirred at 50.degree. C. for 0.5 h. The
mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at
50.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is triturated with Et.sub.2O/heptane overnight. The precipitate is
collected by filtration, washed with H.sub.2O (50 mL) and heptane
(50 mL), and dried in vacuo to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(6-trifluoromethyl-indol-1-yl)-amide (100 mg, 25%). MS: 399 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.16 (s, NH, 1H),
9.39 (s, 1H), 9.06 (d, 2H), 7.92 (s, 1H), 7.81 (m, 2H), 7.70 (t,
1H), 7.44 (d, 1H), 6.74 (d, 1H), 2.79 (s, 3H).
Example 185
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00191##
[1055] Step 1: A solution of
2-iodo-6-trifluoromethyl-pyridin-3-ylamine (5.09 g, 17.7 mmol) in
DCM (50 mL) is treated with TFAA (3 mL, 21.2 mmol) and pyridine
(1.7 mL, 21.2 mmol), and stirred at rt for 1 h. The mixture is
diluted with H.sub.2O (150 mL), and extracted with DCM (3.times.150
mL). The combined organic layer is dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is diluted with
MeCN (50 mL), treated with trans-crotyl bromide (2.8 mL, 26.6 mmol)
and K.sub.2CO.sub.3 (4.7 g, 34.4 mmol), and heated at reflux for 2
h. The mixture is filtered through a pad of Celite. The filtrate is
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 0%-25% EtOAc in heptane to afford
N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-6-trifluoromethyl-pyridin-3-yl)-ac-
etamide (5.5 g, 71%). MS: 439 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.71 (d, 1H), 7.53 (d, 1H), 5.52 (m, 2H), 4.98
(m, 1H), 3.58 (m, 1H), 1.68 (d, 3H).
[1056] Step 2: A solution of
N-but-2-enyl-2,2,2-trifluoro-N-(2-iodo-6-trifluoromethyl-pyridin-3-yl)-ac-
etamide (5.2 g, 11.9 mmol) in DMF (24 mL) is treated with
n-Bu.sub.4NCl (3.6 g, 13.1 mmol), Pd(OAc).sub.2 (107 mg, 0.48
mmol), and stirred at 100.degree. C. for 1 h. H.sub.2O (10 mL) is
added, and the mixture is cooled to rt and filtered through a pad
of silica gel. The filtrate is extracted with EtOAc/heptane
(3.times.50 mL) (1:1). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 5%-50% EtOAc
in heptane to afford
3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2.2 g, 86%).
MS: 215 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.24 (s,
NH, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.34 (d, 1H), 2.93 (q, 2H),
1.36 (t, 3H).
[1057] Step 3: A suspension of NaH (4.65 g, 116 mmol, 60% in
mineral oil) in DMF (40 mL) at 0.degree. C. is treated with
3-ethyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine (2 g, 7.75
mmol) and stirred at 0.degree. C. for 1 h. The mixture is treated
with HOSA (4.4 g, 38.8 mmol) portion wise and warmed to rt over 2
h. The mixture is then poured over ice, treated with solid
NH.sub.4Cl (3 g), and filtered through a pad of Celite. The
filtrate is extracted with Et.sub.2O (3.times.150 mL). The combined
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 30%-50% EtOAc in heptane to afford
3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.5 g,
84%). MS: 230 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
7.97 (d, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 6.12 (s, NH.sub.2, 2H),
2.78 (q, 2H), 1.28 (t, 3H).
[1058] Step 4: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg,
1.1 mmol) and
3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (230 mg,
1 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at
50.degree. C. overnight. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min. The
precipitate is collected by filtration, washed with H.sub.2O (50
mL) and heptane (50 mL), and dried in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo [32-b]pyridin-1-yl)-amide (195
mg, 44%). MS: 444 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 12.16 (s, NH, 1H), 9.28 (s, 1H), 8.34 (d, 1H), 8.18 (m,
2H), 7.86 (s, 1H), 7.65 (m, 2H), 7.45 (m, 1H), 2.83 (q, 2H), 2.78
(s, 3H), 1.35 (t, 3H).
Example 186
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo [32-b]pyridin-1-yl)-amide
##STR00192##
[1060] A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic
acid (258 mg, 1.1 mmol) and
3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (230 mg,
1.0 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1 h. The
mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at
50.degree. C. overnight. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min. The
precipitate is collected by filtration, washed with H.sub.2O (50
mL) and heptane (50 mL), and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo [32-b]pyridin-1-yl)-amide (175
mg, 41%). MS: 427 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 12.18 (s, NH, 1H), 9.31 (s, 1H), 8.80 (d, 1H), 8.45 (d,
1H), 8.16 (d, 1H), 8.01 (m, 1H), 7.88 (s, 1H), 7.72 (d, 1H), 7.59
(m, 1H), 2.81 (q, 2H), 2.79 (s, 3H), 1.35 (t, 3H).
Example 187
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00193##
[1062] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (88 mg, 0.40
mmol) and 3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine
(89 mg, 0.40 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 1
h. The mixture is treated with DMTMM (113 mg, 0.41 mmol) and
stirred at 50.degree. C. overnight. The mixture is diluted with
saturated aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 10 min.
The precipitate is collected by filtration, washed with H.sub.2O
(50 mL) and heptane (50 mL), and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (75
mg, 40%). MS: 433 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 12.19 (s, NH, 1H), 9.28 (s, 1H), 8.15 (m, 2H), 8.08 (d,
1H), 7.87 (s, 1H), 7.72 (d, 1H), 2.83 (q, 2H), 2.77 (s, 3H), 1.35
(t, 3H).
Example 188
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00194##
[1064] A solution of 4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(259 mg, 1.2 mmol) and
3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (230 mg,
1.0 mmol) in DMF (5 mL) is stirred at 50.degree. C. for 0.5 h. The
mixture is treated with DMTMM (290 mg, 1.05 mmol) and stirred at
50.degree. C. overnight. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by preparative reverse-phase HPLC eluting with 20%-100%
MeCN in H.sub.2O to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-ethyl-5-trifluoromethyl-pyrrolo [32-b]pyridin-1-yl)-amide (230
mg, 54%). MS: 428 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.28 (s, 1H), 9.05 (d, 2H), 8.11 (d, 1H), 7.98 (s, 1H),
7.69 (t, 1H), 7.64 (d, 1H), 2.83 (q, 2H), 2.80 (s, 3H), 1.34 (t,
3H).
Example 189
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-2-methyl-indol-1-yl)-amide
##STR00195##
[1066] Step 1: A suspension of NaH (1.25 g, 51 mmol, 60% in mineral
oil) in DMF (47 mL) at 0.degree. C. is treated with
5-methoxy-2-methylindole (500 mg, 3.1 mmol) and stirred at
0.degree. C. for 0.5 h. The mixture is treated with HOSA (1.92 g,
17.0 mmol) portion wise and warmed to rt over 2 h. The mixture is
then poured over ice, and extracted with EtOAc (3.times.50 mL). The
combined organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford 5-methoxy-2-methyl-indol-1-ylamine,
which is used in the next step without further purification.
[1067] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (719 mg,
3.1 mmol) and 5-methoxy-2-methyl-indol-1-ylamine (550 mg, 3.1 mmol)
in DMF (4 mL) is stirred at 50.degree. C. for 15 min. The mixture
is treated with DMTMM (856 mg, 3.1 mmol) and stirred at 50.degree.
C. for 1 h. The mixture is concentrated in vacuo, diluted with
EtOAc (50 mL), and washed with saturated aqueous Na.sub.2CO.sub.3
(50 mL). The organic layer is separated, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 30% EtOAc in heptane to
afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-2-methyl-indol-1-yl)-amide (180 mg, 15%, 2 steps). MS:
391 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.23 (s,
1H), 8.34 (d, 1H), 8.18 (d, 1H), 7.63 (m, 1H), 7.46 (m, 1H), 7.31
(d, 1H), 7.02 (d, 1H), 6.77 (m, 1H), 6.25 (s, 1H), 3.76 (s, 3H),
2.77 (s, 3H), 2.34 (s, 3H).
Example 190
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
N',N'-diphenyl-hydrazide
##STR00196##
[1069] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (500 mg,
2.2 mmol) and N,N-diphenyl-hydrazine (422 mg, 2.2 mmol) in DMF (3
mL) is stirred at 50.degree. C. for 15 min. The mixture is treated
with DMTMM (633 mg, 2.2 mmol) and stirred at 50.degree. C. for 3 h.
The mixture is diluted with EtOAc (50 mL), and washed with
saturated aqueous Na.sub.2CO.sub.3 (50 mL). The organic layer is
separated, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 75% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
N',N'-diphenyl-hydrazide (60 mg, 7%). MS: 399 (M+H); .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 9.04 (s, 1H), 8.30 (d, 1H), 8.15
(m, 1H), 7.61 (m, 1H), 7.44 (m, 1H), 7.35 (m, 4H), 7.22 (m, 4H),
7.04 (m, 2H), 2.64 (s, 3H). IC.sub.50=16 nM.
Example 191
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(7-fluoro-3-methyl-indol-1-yl)-amide
##STR00197##
[1071] Step 1: A suspension of NaH (805 mg, 20.1 mmol, 60% in
mineral oil) in DMF (5 mL) at 0.degree. C. is treated with
7-fluoro-3-methylindole (200 mg, 1.34 mmol) and stirred at
0.degree. C. for 1 h. The mixture is treated with HOSA (757 mg, 6.7
mmol) portion wise and warmed to rt over 2 h. The mixture is then
poured over ice, and extracted with EtOAc (3.times.100 mL). The
combined organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford 7-fluoro-3-methyl-indol-1-ylamine,
which is used in the next step without further purification.
[1072] Step 2: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34
mmol) and 7-fluoro-3-methyl-indol-1-ylamine (342 mg, 1.47 mmol) in
DMF (15 mL) is stirred at 50.degree. C. for 1 h. The mixture is
treated with DMTMM (407 mg, 1.47 mmol) and stirred at 50.degree. C.
for 4 h. The mixture is concentrated in vacuo, diluted with
Et.sub.2O (50 mL), and washed with saturated aqueous
Na.sub.2CO.sub.3 (50 mL). The organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0%-100% DCM
in EtOAc to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(7-fluoro-3-methyl-indol-1-yl)-amide (241 mg, 48%). MS: 379 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.05 (s, 1H), 8.32 (d,
1H), 8.18 (d, 1H), 7.64 (m, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.31
(s, 1H), 7.05 (m, 2H), 2.74 (s, 3H), 2.29 (s, 3H).
Example 192
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-3-methyl-indol-1-yl)-amide
##STR00198##
[1074] Step 1: A solution of
allyl-(2-iodo-4-methanesulfonyl-phenyl)-amine (1.43 g, 4.1 mmol) in
DMF (20 mL) is treated with n-Bu.sub.4NCl (1.47 g, 5.32 mmol),
Pd(OAc).sub.2 (56.6 mg, 0.2 mmol), and stirred at 100.degree. C.
for 1 h. HCl (5.3 mL, 3 M) is added, and the mixture is cooled to
rt, filtered through a pad of Celite, and extracted with EtOAc
(3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 60% EtOAc in
heptane to afford 5-methanesulfonyl-3-methyl-1H-indole (370 mg,
43%).
[1075] Step 2: A suspension of NaH (1.06 g, 26.6 mmol, 60% in
mineral oil) in DMF (15 mL) at 0.degree. C. is treated with
5-methanesulfonyl-3-methyl-1H-indole (370 mg, 1.77 mmol) and
stirred at 0.degree. C. for 1 h. The mixture is treated with HOSA
(1 g, 8.85 mmol) portion wise and warmed to rt overnight. The
mixture is then poured over ice, and extracted with EtOAc
(3.times.100 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
5-methanesulfonyl-3-methyl-indol-1-ylamine, which is used in the
next step without further purification.
[1076] Step 3: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.77
mmol) and 5-methanesulfonyl-3-methyl-indol-1-ylamine (452 mg, 1.95
mmol) in DMF (15 mL) is stirred at rt for 1 h. The mixture is
treated with DMTMM (538 mg, 1.95 mmol) and stirred at 60.degree. C.
for 1.5 h. The mixture is diluted with EtOAc (50 mL), and washed
with saturated aqueous Na.sub.2CO.sub.3 (50 mL). The organic layer
is separated, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue is purified by silica gel chromatography
eluting with 0%-100% EtOAc in heptane, and then by triturating in
Et.sub.2O to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methanesulfonyl-3-methyl-indol-1-yl)-amide (106 mg, 14%). MS:
439 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.15 (s,
1H), 8.37 (d, 1H), 8.24 (m, 2H), 7.82 (m, 1H), 7.59 (d, 1H), 7.54
(m, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 3.13 (s, 3H), 2.83 (s, 3H),
2.42 (s, 3H).
Example 193
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide trifluoroacetic acid
salt
##STR00199##
[1078] Step 1: (Ref.: J. Org. Chem. 2002, 67, 6226-6227)
7-Azaindole (5 g, 42.3 mmol) is added to a stirred suspension of
AlCl.sub.3 (22.6 g, 169 mmol) in DCM (300 mL). After stirring at rt
for 1 h, acetyl chloride (13.3 g, 169 mmol) is added drop wise and
the resulting mixture is stirred for 18 h. The mixture is cooled to
0.degree. C., quenched with MeOH (150 mL) and stirred for 1 h.
Silica gel is added to the mixture, the solvents are removed under
vacuum, and the residue is purified by silica gel chromatography
eluting with 10% MeOH in DCM to afford
1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (1.6 g). .sup.1H NMR
(300 MHz, CH.sub.3OD): .delta. 8.93 (d, 1H), 8.45 (s, 2H), 7.50 (t,
1H), 3.30 (s, 3H).
[1079] Step 2: To a solution of
1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethanone (1.34 g, 8.38 mmol) in
TFA (25 mL) is added triethylsilane (6.09 g, 52.4 mmol) and stirred
at rt for 18 h. The mixture is concentrated, diluted with 2 N
aqueous KOH solution and extracted three times with DCM. The
combined organic layer is dried (Na.sub.2SO.sub.4), filtered and
evaporated. The resulting residue is chromatographed through silica
gel eluting with 10% MeOH in DCM to afford
3-ethyl-1H-pyrrolo[2,3-b]pyridine (0.91 g). MS: 147 (M+H); .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 9.23 (broad s, 1H), 8.32 (d,
1H), 7.94 (s, 1H), 7.05-7.14 (m, 2H), 2.80 (q, 2H), 1.35 (t,
3H).
[1080] Step 3: 3-Ethyl-1H-pyrrolo[2,3-b]pyridine (0.91 g, 6.2 mmol)
and KOtBu (1.39 g, 12.4 mmol) are dissolved in DMF (28 mL) and
stirred for 2 h at rt. While vigorously sparging with nitrogen,
NH.sub.2Cl (92 ml 0.15 M in ether) is added in portions. The
reaction mixture is stirred at rt for 2 h. The mixture is cooled
0.degree. C. and then quenched with Na.sub.2S.sub.2O.sub.3 (2.7 g)
in water (50 mL). After standing at rt for 18 h, the mixture is
concentrated, triturated in DCM and filtered. The filtrate is
concentrated and chromatographed through silica gel eluting with
10% MeOH in DCM to afford 3-ethyl-pyrrolo[2,3-b]pyridin-1-yl-amine
(380 mg). MS: 162 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.32 (d, 1H), 7.90 (d, 1H), 7.04-7.13 (m, 2H), 4.96 (broad s, 2H),
2.76 (q, 2H), 1.33 (t, 3H).
[1081] Step 4. A mixture of 3-ethyl-pyrrolo[2,3-b]pyridin-1-ylamine
(126 mg, 0.78 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (168 mg, 0.78
mmol), HATU (356 mg, 0.936 mmol) and DIPEA (302 mg, 2.34 mmol) in
DMF (4 mL) is heated at 150.degree. C. for 1 h. The reaction is
quenched with water and extracted with EtOAC. The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
first chromatographed through silica gel eluting with 10% MeOH in
DCM. The resulting product is chromatographed again using reverse
phase HPLC eluting with 0.1% TFA in water and acetonitrile to
afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide trifluoroacetic acid
salt (29 mg). MS: 359 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 9.45 (s, 1H), 9.04 (d, 1H), 8.93 (d, 1H), 8.67 (t, 1H),
8.31 (d, 1H), 8.19-8.08 (m, 2H), 7.34 (s, 1H), 7.27 (dd, 1H), 2.96
(s, 3H), 2.85 (q, 2H), 1.39 (t, 3H).
Example 194
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide
##STR00200##
[1083] A mixture of 3-ethyl-pyrrolo[2,3-b]pyridin-1-ylamine (126
mg, 0.78 mmol),
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (180 mg,
0.78 mmol), HATU (356 mg, 0.036 mmol) and DIPEA (302 mg, 2.34 mmol)
in DMF (4 mL) is heated at 150.degree. C. for 1 h. The reaction is
quenched with water and extracted with EtOAc. The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
chromatographed through silica gel eluting with 0-100% ethyl
acetate in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide (128 mg). MS: 376 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.10 (s, 1H),
8.25-8.33 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62 (q, 1H),
7.39-7.48 (m, 2H), 7.16 (dd, 1H), 2.78 (s, 3H), 2.75 (q, 2H), 1.29
(t, 3H).
Example 195
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3c]pyridin-1-yl)-amide
##STR00201##
[1085] A mixture of 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (93 mg,
0.577 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid (134 mg, 0.757 mmol), HATU (263 mg, 0.692 mmol) and DIPEA (223
mg, 1.73 mmol) in DMF (3 mL) is heated at 150.degree. C. for 1 h.
The reaction is quenched with water and extracted with EtOAc. The
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue is purified by silica gel column
chromatography eluting with 0-100% ethyl acetate in heptane to
afford 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (86 mg). MS: 376 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.15 (s, 1H), 8.69 (s,
1H), 8.37 (d, 1H), 8.15-8.26 (m, 2H), 7.70 (d, 1H), 7.55 (q, 1H),
7.49 (s, 1H), 7.29 (t, 1H), 2.80-2.90 (m, 5H), 1.38 (t, 3H).
IC.sub.50=7 nM.
Example 196
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide trifluoroacetic acid
salt
##STR00202##
[1087] Step 1: (Ref.: J. Org. Chem. 2002, 67, 6226-6227)
6-Azaindole (2.5 g, 21.25 mmol) is added to a stirred suspension of
AlCl.sub.3 (11.3 g, 84.5 mmol) in CH.sub.2Cl.sub.2 (150 mL). After
stirring at rt for 1 h, acetyl chloride (6.65 g, 84.5 mmol) is
added drop wise and the resulting mixture is stirred for 18 h. The
mixture is cooled to 0.degree. C., quenched with MeOH (75 mL) and
stirred for 1 h. Silica gel (40 mL), MeOH and DCM are added to the
mixture, the solvents are removed under vacuum and the residue is
purified by silica gel chromatography eluting with 10% MeOHl in DCM
to afford 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (1.52 g, 45%).
MS: 161 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.20 (s,
1H), 8.95 (s, H), 7.82 (d, 1H), 8.72 (d, 1H), 8.43 (d, 1-H), 2.64
(s, 3H).
[1088] Step 2: To a solution of
1-(1H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (1.53 g, 9.55 mmol) in
TFA (29 mL) triethylsilane (6.88 g, 59.21 mmol) is added and
stirred at rt for 18 h. The mixture is concentrated and extracted
with EtOAc. The organic layer is washed with 2 N aqueous KOH, dried
(Na.sub.2SO.sub.4), filtered and evaporated. The residue is
chromatographed through silica gel eluting with 10% MeOH in DCM to
afford 3-ethyl-1H-pyrrolo[2,3-c]pyridine (1.35 g, 97%). MS: 147
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 13.3 (broad,
N--H) 9.46 (s, 1H), 8.04 (s, 1H), 7.71-7.88 (m, 2H), 2.88 (q, 2H),
1.39 (t, 3H).
[1089] Step 3: 3-Ethyl-1H-pyrrolo[2,3-c]pyridine (1.21 g, 8.29
mmol) and KOtBu (1.86 g, 16.57 mmol) are dissolved in DMF (47 mL)
and stirred for 2 h at rt. While vigorously purging with nitrogen,
NH.sub.2Cl (101 mL 0.15 M in ether) is added in portions. The
reaction mixture is stirred at rt for 1 h. The mixture is then
cooled to 0.degree. C. and quenched with Na.sub.2S.sub.2O.sub.3
(4.3 g) in water (80 mL). After standing at rt for 2 days, the
layers are separated. Brine is added to the aqueous layer and then
extracted with EtOAc. The organic layers are combined and dried
(Na.sub.2SO.sub.4) to give a mixture of
3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine and starting material. This
mixture is purified by chromatography through silica gel eluting
with 10% MeOH in DCM to afford
3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (93 mg). The remaining
mixture of starting material and product is collected and dissolved
in DCM. This solution is cooled to 0.degree. C. and charged with
BOC.sub.2O (164 mg, 0.75 mmol). The resulting mixture is purified
by silica gel chromatography eluting with 10% MeOH in DCM to afford
additional 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine (145 mg).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.85 (s, 1H), 8.25 (d,
1H), 7.48 (d, 1H), 7.10 (s, 1H), 4.88 (s, 2H), 2.75 (q, 2H), 1.35
(t, 3H).
[1090] Step 4. A mixture of 3-ethyl-pyrrolo[2,3-c]pyridin-1-ylamine
(122 mg, 0.757 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (163 mg, 0.757
mmol), HATU (356 mg, 0.936 mmol) and DIPEA (294 mg, 2.27 mmol) in
DMF (4 mL) is heated at 150.degree. C. for 1 h. The reaction is
quenched with water and the extracted with EtOAc. The organic layer
is dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
is chromatographed through silica gel eluting with 10% MeOH in DCM.
The resulting product is chromatographed again using reverse phase
HPLC eluting with 0.1% TFA in water and acetonitrile to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide trifluoroacetic acid
salt (42 mg, 9.5%). MS: 359 (M+H); .sup.1H NMR (300 MHz,
DMSO-d.sup.6): .delta. 9.43 (s, 1H), 9.37 (s, 1H), 8.80 (d, 1H),
8.45 (t, 2H), 8.26 (s, 1H), 8.22 (d, 1H), 8.03 (t, 1H), 7.59 (t,
1H), 2.86 (q, 2H), 2.80 (s, 3H), 1.32 (t, 3H).
Example 197
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo [32-b]pyridin-1-yl)-amide
##STR00203##
[1092] A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (75%
pure) (240 mg, <1.63 mmol),
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg,
1.63 mmol), HATU (744 mg, 1.96 mmol) and DIPEA (388 mg, 4.89 mmol)
in DMF (5 mL) is heated at 150.degree. C. for 1 h. The reaction is
quenched with water, extracted with EtOAc. The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
chromatographed through silica gel eluting with 10% MeOH in DCM.
The resulting product is recrystallized with ether to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (197 mg, 44%). MS: 362
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.14 (s, 1H),
8.40 (d, 1H), 8.36 (d, 1H), 8.22 (d, 1H), 7.85 (d, 1H), 7.55 (q
1H), 7.47 (s, 1H), 7.25-7.34 (m, 2H), 2.83 (s, 3H), 2.42 (s, 3H).
IC.sub.50=2 nM.
Example 198
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-5-trifluoromethyl-indol-1-yl)-amide
##STR00204##
[1094] Step 1: To a mixture of 2-iodo-4-trifluoromethyl-aniline (5
g, 17.4 mmol), KOt-Bu (2.05 g, 18.3 mmol) and THF (200 mL) at
-78.degree. C., is added allyl bromide (2.21 g, 18.3 mmol). The
resulting mixture is warmed to rt and stirred for 18 h. Water is
added, and the mixture is extracted with EtOAc. The organic layer
is separated, dried (Na.sub.2SO.sub.4), filtered and concentrated.
The residue is chromatographed through silica gel eluting with
0-50% EtOAc in heptane to afford
allyl-(2-iodo-4-trifluoromethyl-phenyl)-amine (1.9 g, 33%). MS 328
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.90 (s, 1H),
7.45 (d, 1H), 5.88-6.02 (m, 1H), 5.33 (d, 1H), 5.25 (d, 1H), 4.72
(broad s, 1H), 3.90 (s, 2H).
[1095] Step 2: A mixture of
allyl-(2-iodo-4-trifluoromethyl-phenyl)-amine (1.75 g, 5.35 mmol),
tetrabutylammonium chloride (1.68 g, 5.35 mmol), palladium acetate
(120 mg, 0.54 mmol) and potassium carbonate (2.22 g, 16.0 mmol) in
DMF (50 mL) is heated at 80.degree. C. for 1.5 h. The reaction is
quenched with water and extracted three times with DCM. The
combined organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue is chromatographed through silica gel
eluting with 0-40% EtOAc in heptane to afford
3-methyl-5-trifluoromethyl-1H-indole (401 mg). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta.=8.09 (broad s, 1H), 7.90 (s, 1H), 7.44
(s, 1H), 7.10 (s, 1H), 2.38 (s, 3H).
[1096] Step 3: 60% NaH (1.21 g, 30.2 mmol) is added to a stirred
solution of 3-methyl-5-trifluoromethyl-1H-indole (400 mg, 2.01
mmol) in DMF (6 mL) at 0.degree. C. in portions. The mixture is
stirred at 0.degree. C. for 1 h. HOSA (1.14 g, 10.0 mmol) is added
in portions at 0.degree. C. and the mixture is allowed to warm to
rt over 2 h. The reaction is quenched with aqueous saturated
ammonium chloride, extracted with extracted three times with DCM.
The combined organic layer is dried (Na.sub.2SO.sub.4), filtered
and concentrated. The residue is chromatographed through silica gel
eluting with 0-40% EtOAc in heptane to afford
3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 52%). MS: 215
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=7.84 (s, 1H),
7.48 (s, 2H), 7.04 (s, 1H), 4.77 (s, 2H), 2.34 (s, 3H).
[1097] Step 4: A mixture of
3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 1.04 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (224 g, 1.04
mmol), HATU (475 mg, 1.25 mmol), DIPEA (404 mg 3.13 mmol) is
stirred in DMF at 150.degree. C. for 1 h. The reaction is quenched
with water, extracted with extracted with EtOAc. The organic layer
is dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
is chromatographed through silica gel eluting with 10% MeOH in DCM
to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-5-trifluoromethyl-indol-1-yl)-amide (122 mg, 28%). MS:
412 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.22 (s, 1H),
8.79 (d, 1H), 8.66 (d, 1H), 8.06 (t, 1H), 7.91 (s, 1H), 7.60 (dd,
1H), 7.51 (s, 2H), 7.29 (s, 3H), 2.88 (s, 3H), 2.40 (s, 3H).
Example 199
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00205##
[1099] Step 1: To a solution of 3-amino-2-chloropyridine (5 g 38.9
mmol) in THF (35 mL) is added 2 M NaHMDS in THF (38.9 mL, 77.8
mmol). After stirring at rt for 15 min, BOC.sub.2O (7.7 g, 35.6
mmol) in THF (20 mL) is added in one portion and then stirred for 5
h at rt. 0.1% aqueous HCl is added. The mixture is extracted with
EtOAc. The organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue is chromatographed through silica gel
eluting with 0-50% EtOAc in heptane to afford
(2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (7.18 g,
89%). MS: 229 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.52 (d, 1H), 8.05 (dd, 1H), 7.23 (dd, 1H), 7.02 (broad s, 1H),
1.55 (s, 9H)).
[1100] Step 2: A mixture of (2-chloro-pyridin-3-yl)-carbamic acid
tert-butyl ester (7 g, 30.7 mmol), allyl bromide (5.26 g, 40.8
mmol) and cesium carbonate (20.8 g, 63.8 mmol) in DMF (280 mL) is
heated at 60.degree. C. for 1 h. The reaction is quenched with
water, extracted with EtOAC. The organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated to afford
allyl-(2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (8.03
g, 98%), which is sued in the next step with no further
purification.
[1101] Step 3: A mixture of allyl-(2-chloro-pyridin-3-yl)-carbamic
acid tert-butyl ester (8.03 g, 30 mmol), tetrabutylammonium
chloride (9.4 g, 30 mmol), palladium acetate (673 mg, 3 mmol) and
potassium carbonate (12.4 g, 3 mmol) in DMF (300 mL) is heated at
80.degree. C. for 1.5 h. The reaction is quenched with DCM and
washed with water. The organic layer is dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue is chromatographed through
silica gel eluting with 0-40% EtOAc in heptane to afford
3-methyl-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester
and 3-methylene-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic
acid tert-butyl ester (1.58 g).
[1102] Step 4: The above mixture is then stirred in DCM (10 mL) and
TFA (10 mL) at rt for 3 h. The reaction is concentrated, and 2 M
KOH aqueous solution and DCM are added. The precipitate is
collected by filtration to afford
3-methyl-1H-pyrrolo[3,2-b]pyridine potassium salt (1 g, 20%). MS:
133 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.26 (d, 1H),
7.75 (d, 1H), 7.33 (s, 1H), 7.12 (dd, 1H), 2.36 (s, 3H).
[1103] Step 5: A mixture of 3-methyl-1H-pyrrolo[3,2-b]pyridine
potassium salt (1 g, 5.88 mmol), KOtBu (660 mg, 5.88 mmol) in DMF
(26 mL) is purged with N.sub.2 and stirred at rt for 2 h.
Chloramine in ether (0.15 M, 29 mL) is added and the mixture is
stirred for 45 min. The reaction is cooled to 0.degree. C.,
Na.sub.2S.sub.2O.sub.3 (3.4 g) in water (70 mL) is added and the
mixture is stirred for 15 min. The mixture is concentrated in
vacuo. The residue is triturated with DCM and then filtered. The
filtrate is washed with 2 M aqueous KOH, dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue is chromatographed through
silica gel eluting with 10% MeOH in DCM to afford a mixture of
starting material and 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine
(839 mg, 64%, 66 mol % pure), which is used in the next step
without further purification.
[1104] Step 6: A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl
amine (839 mg, <5.71 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (1.32 g, 6.13
mmol), HATU (2.6 g, 6.85 mmol), DIPEA (2.21 g 17.1 mmol) in DMF (17
mL) is stirred at 150.degree. C. for 1 h. The reaction is quenched
with water and ether. The water layer is concentrated in vacuo. The
residue is chromatographed through silica gel eluting with a
mixture of DCM, MeOH and triethylamine (9.5:0.5:0.05) to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (134 mg). MS: 345 345
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.22 (s, 1H),
8.79 (d, 1H), 8.64 (d, 1H), 8.40 (d, 1H), 8.05 (t, 1H), 7.87 (d,
1H), 7.60 (t, 1H), 7.49 (s, 1H) 7.30 (dd, 1H), 2.87 (s, 3H), 2.42
(s, 3H).
Example 200
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3c]pyridin-1-yl)-amide
##STR00206##
[1106] Step 1: 60% Sodium hydride (6.69 g, 167 mmol) is added to a
stirred solution of 3-methyl-1H-pyrrolo[2,3-c]pyridine (1.47 g,
11.2 mmol) in DMF (33 mL) portion wise at 0.degree. C. for 1 h.
Hydroxylamine-O-sulfonic acid (6.3 g, 55.8 mmol) is added in
portions at 0.degree. C. and stirred for 2 h at 0.degree. C. The
reaction mixture is quenched at 0.degree. C. with water,
concentrated in vacuo to remove DMF. The residue is triturated in
DCM. The solid is filtered off and the filtrate is concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 10% MeOH in DCM to afford
3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (1 g, 61%). MS: 148 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.85 (s, 1H), 8.27 (d,
1H), 7.46 (d, 1H), 7.09 (s, 1H), 2.30 (s, 3H).
[1107] Step 2: A mixture of
3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (224 mg, 1.53 mmol),
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (354 mg,
1.53 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol)
in DMF (8 mL) is stirred at 150.degree. C. for 1 h. The reaction is
quenched with water, extracted with EtOAc. The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with
0-100% EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (55 mg). MS: 362 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.15 (s, 1H), 8.69 (s,
1H), 8.37 (d, 1H), 8.24 (s, 1H), 8.20 (d, 1H), 7.68 (d, 1H), 7.55
(q, 1H), 7.47 (s, 1H), 7.29 (t, 1H), 2.84 (s, 3H), 2.39 (s,
3H).
Example 201
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide
##STR00207##
[1109] Step 1: To a solution of 3-amino-4-chloropyridine (6.56 g,
51 mmol) in THF (46 mL) is added 2 M NaHMDS in THF (50 mL, 100
mmol). After stirring at rt for 15 min BOC.sub.2O (10.1 g, 46.4
mmol) in THF (26 mL) is added in one portion and the mixture is
stirred for 3 h at rt. 0.1% aqueous HCl (590 mL) is added. The
mixture is extracted with EtOAc. The organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
purified by silica gel chromatography eluting with 0-50% EtOAc in
heptane to afford (4-chloro-pyridin-3-yl)-carbamic acid tert-butyl
ester (6.78 g, 76%). MS: 229 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 9.38 (ms 1H), 8.23 (d, 1H), 7.30 (dd, 1H),
6.85 (broad s, 1H), 1.57 (s, 9H).
[1110] Step 2: A mixture of (4-chloro-pyridin-3-yl)-carbamic acid
tert-butyl ester (6.78 g, 29.7 mmol), allyl bromide (5.1 g, 40.8
mmol) and cesium carbonate (20.1 g, 61.8 mmol) in DMF (200 mL) is
heated at 60.degree. C. for 1 h. The reaction is quenched with
water, extracted with EtOAc. The organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
purified by silica gel column chromatography eluting with 0-40%
EtOAc in heptane to afford allyl-(4-chloro-pyridin-3-yl)-carbamic
acid tert-butyl ester (5.66 g, 71%). MS: 269 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 8.42 (d, 1H), 7.40 (d, 1H),
5.80-5.98 (m, 1H), 4.35-4.51 (m, 1H), 3.90-4.07 (m, 1H).
[1111] Step 3: A mixture of allyl-(4-chloro-pyridin-3-yl)-carbamic
acid tert-butyl ester (7.68 g, 28.7 mmol), tetrabutylammonium
chloride (9.0 g, 28.7 mmol), palladium acetate (643 mg, 2.87 mmol)
and potassium carbonate (11.9 g, 86.0 mmol) in DMF (200 mL) is
heated at 80.degree. C. for 1.5 h. The reaction mixture is diluted
with DCM and washed three times with water. The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
purified by silica gel column chromatography eluting with 0-40%
EtOAc in heptane to afford a mixture of
3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester
and 3-methylene-2,3-dihydro-pyrrolo[2,3-c]pyridine-1-carboxylic
acid tert-butyl ester (3.1 g total).
[1112] Step 4: The above mixture is stirred in DCM (10 mL) and TFA
(10 mL) at rt for 18 h and then concentrated in vacuo. 2 M aqueous
KOH is added. The mixture is extracted with EtOAC. The organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated. The
residue is purified by silica gel column chromatography eluting
with 10% MeOH in DCM to afford 3-methyl-1H-pyrrolo[2,3-c]pyridine
(1.98 g, 69%). MS: 133 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 9.10 (broad s, 1H), 8.79 (s, 1H), 8.28 (d, 1H), 7.52 (d,
1H), 7.20 (s, 1H) 2.36 (s, 2H).
[1113] Step 5: A mixture of 3-methyl-1H-pyrrolo[2,3-c]pyridine
(1.21 g, 9.16 mmol), KOtBu (2.05 g, 18.3 mmol) in DMF (41 mL) is
purged with N.sub.2 and stirred at rt for 2 h. Chloramine in ether
(0.15 M, 92 mL) is added and the mixture is stirred for 20 min. The
reaction is cooled to 0.degree. C. and a solution of
Na.sub.2S.sub.2O.sub.3 (5 g) in water (80 mL) is added. The mixture
is stirred for 10 min, and then concentrated in vacuo. The residue
is triturated in DCM and filtered. DCM is added, cooled to
0.degree. C. and charged with BOC.sub.2O (541 mg, 2.48 mmol). The
resulting mixture is separated by silica gel chromatography eluting
with 10% MeOH in DCM to afford 3-methyl-pyrrolo[2,3-c]pyridin-1-yl
amine (468 mg, 35%). MS: 148 (M+H); .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 8.85 (s, 1H), 8.27 (d, 1H), 7.46 (d, 1H), 7.09
(s, 1H), 2.30 (s, 3H).
[1114] Step 6: A mixture of 3-methyl-pyrrolo[2,3-c]pyridin-1-yl
amine (467 mg, 3.18 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (683 g, 3.18
mmol), HATU (1.45 g, 3.81 mmol), DIPEA (1.23 g 9.54 mmol) in DMF
(10 mL) is stirred at 150.degree. C. for 1 h. The reaction is
quenched with water, and NaHCO.sub.3 (320 mg, 3.81 mmol) and EtOAC
are added. The resulting solid is collected by filtration and then
triturated with hot water. The mixture is filtered again and the
solid is dried under vacuum to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (484 mg). MS: 345
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.24 (s, 1H),
8.79 (d, 2H), 8.65 (d, 1H), 8.21 (d, 1H), 8.05 (t, 1H), 7.72 (d,
1H), 7.60 (s, 1H), 7.57 (s, 1H), 2.88 (s, 3H), 2.40 (s, 3H).
Example 202
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo [3,2-c]pyridin-1-yl)-amide
##STR00208##
[1116] Step 1: To a solution of 4-amino-3-chloropyridine (15 g,
116.7 mmol) in THF (60 mL) is added NaHMDS in THF (1 M, 233. mL,
233 mmol). After stirring at rt for 30 min, BOC.sub.20 (23.2 g, 106
mmol) in THF (45 mL) is added in one portion and the mixture is
stirred for 3 h at rt. Additional BOC.sub.2O (2 g, 9.0 mmol) in THF
(40 mL) is added and the reaction is stirred for 18 h at rt. 0.1%
aqueous HCl (1.35 L) is added. The mixture is extracted with EtOAc.
The organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue is recrystallized from ether to afford
(3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (4 g). The
mother liquor is purified by silica gel column chromatography
eluting with 0-50% EtOAc in heptane. The collected product is
crystallized from ether to afford additional 4.5 g of
(3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (total yield
8.5 g). MS: 229 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.48 (s, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.18 (broad s, 1H) 1.57
(s, 9H).
[1117] Step 2: A mixture of (3-chloro-pyridin-3-yl)-carbamic acid
tert-butyl ester (8.4 g, 36.8 mmol), allyl bromide (7.46 g, 39.1
mmol) and cesium carbonate (24.9 g, 76.4 mmol) in DMF (100 mL) is
heated at 60.degree. C. for 1 h. The reaction is quenched with
water, extracted with EtOAc. The organic layer is dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-40%
EtOAc in heptane to afford allyl-(3-chloro-pyridin-3-yl)-carbamic
acid tert-butyl ester (8.4 g, 85%). MS: 269 (M+H); .sup.1H NMR (300
MHz, CDCl.sub.3): .delta.=8.66 (s, 1H), 8.49 (d, 1H), 7.18 (d, 1H),
5.80-5.96 (m, 1H) 5.15 (s, 1H), 5.10 (d, 1H), 4.2 (broad s, 1H),
1.43 (s, 9H).
[1118] Step 3: A mixture of allyl-(3-chloro-pyridin-4-yl)-carbamic
acid tert-butyl ester (8.25 g, 30.8 mmol), tetrabutylammonium
chloride (9.67 g, 30.8 mmol), palladium acetate (691 mg, 3.08 mmol)
and potassium carbonate (12.8 g, 92.3 mmol) in DMF (100 mL) is
heated at 80.degree. C. for 1.5 h. The reaction is diluted with DCM
and washed three times with water. The organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
chromatographed through silica gel eluting with 0-40% EtOAc in
heptane to afford a mixture 3-methyl-pyrrolo
[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and
3-methylene-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid
tert-butyl ester (4.21 g, total).
[1119] Step 4: The mixture from step 3 is stirred in DCM (10 mL)
and TFA (10 mL) at rt for 18 h.
[1120] The reaction is concentrated. 2 M aqueous KOH solution is
added, and the mixture is extracted with EtOAc. The organic layer
is dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue
is chromatographed through silica gel eluting with 10% MeOH in DCM
to afford of 3-methyl-1H-pyrrolo[3,2-c]pyridine (1.91 g, 47%). MS:
133 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.89 (s, 1H),
8.24 (d, 1H), 7.37 (d, 1H), 7.11 (s, 1H) 2.40 (s, 3H).
[1121] Step 5: A mixture of 3-methyl-1H-pyrrolo[3,2-c]pyridine
(1.91 g, 14.47 mmol) and KOtBu (3.25 g, 28.9 mmol) in DMF (65 mL)
is purged with N.sub.2 and stirred at rt for 2 h. Chloramine in
ether (0.15 M, 145 mL) is added and the mixture is stirred for 20
min. The reaction is cooled to 0.degree. C. and a solution of
Na.sub.2S.sub.2O.sub.3 (800 mg) in water (130 mL) is added. The
mixture is stirred for 10 min at 0.degree. C., and then
concentrated in vacuo. The residue is triturated in DCM and
filtered. DCM is added to the filtrate, cooled to 0.degree. C. and
treated with BOC.sub.2O (793 mg, 3.6 mmol). The mixture is
concentrated in vacuo, and the residue is purified by silica gel
chromatography eluting with 10% MeOH in DCM to afford
3-methyl-pyrrolo [3,2-c]pyridin-1-yl amine (842 mg, 35%). MS: 148
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.85 (s, 1H),
8.36 (d, 1H), 7.32 (d, 1H), 6.95 (s, 1H) 4.77 (s, 2H), 2.37 (s,
3H).
[1122] Step 6: A mixture of 3-methyl-pyrrolo[3,2-c]pyridin-1-yl
amine (223 mg, 1.52 mmol),
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (329 mg, 1.52
mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol) in
DMF (8 mL) is stirred at 150.degree. C. for 1 h. The reaction is
quenched with water and NaHCO.sub.3 (168 mg, 2 mmol). The mixture
is concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 10% meOH in DCM to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide (91 mg, 17%). MS: 345
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.=9.34 (s, 2H),
8.79 (d, 1H), 8.53 (d, 1H), 8.45 (d, 1H), 8.13 (d, 1H), 8.02 (t,
1H), 7.86 (s, 1H), 7.59 (t, 1H), 2.77 (s, 3H), 2.43 (s, 3H).
Example 203
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo [3,2-c]pyridin-1-yl)-amide
##STR00209##
[1124] A mixture of 3-methyl-pyrrolo[3,2-c]pyridin-1-ylamine (224
mg, 1.52 mmol),
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (354 mg,
1.52 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol)
in DMF (8 mL) is heated at 150.degree. C. for 1 h. The reaction is
quenched with water, NaHCO.sub.3 (168 mg, 2 mmol) is added and the
mixture is extracted with EtOAc. The organic layer is separated,
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
first purified by silica gel column chromatography eluting with 10%
MeOH in DCM and then recrystallized from EtOAc to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide (198 mg). MS: 362
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 9.12 (s, 1H),
8.86 (s, 1H), 8.35 (d, 1H), 8.15-8.31 (m, 2H), 7.47-7.60 (m, 2H),
7.35 (s, 1H), 7.29 (t, 1H), 2.84 (s, 3H), 2.44 (s, 3H).
Example 204
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-nitro-indol-1-yl)-amide
##STR00210##
[1126] Step 1: NaH (60%, 421.5 mmol) is added portion-wise to a
solution of 5-nitro-1H-indole (28.1 mmol) in anhydrous DMF (80 mL)
at 0.degree. C. and the mixture is stirred at 0.degree. C. under
N.sub.2 for 10 min. HOSA (140.5 mmol) is added portion-wise for 30
minutes and the mixture is stirred at 0.degree. C. for 2 h. The
reaction is quenched with water. Additional water (250 mL) is added
and the mixture is extracted with EtOAc (3.times.100 mL). The
combined organic layer is washed with water (2.times.30 mL), brine
(30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated. The
residue is washed with heptane (2.times.20 mL) and recrystallized
from EtOAc to afford 5-nitro-indole-1-ylamine (4.84 g, 97%) as a
solid. MS: 178 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
4.93 (br, 2N--H), 6.62 (d, H), 7.30 (d, H), 7.52 (d, H), 8.17 (d,
H), 8.58 (s, H).
[1127] Step 2: DIPEA (12.65 mmol) is added a solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (4.22
mmol), 5-nitro-indole-1-ylamine (4.22 mmol) and HOTT
(S-(1-oxido-2-pyridyl)-thio-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (7.6 mmol) in anhydrous DMF (15 mL) and the
mixture is heated at 80-90.degree. C. overnight. After evaporation
of solvent, the residue is dissolved in EtOAc (150 mL), washed with
water (20 mL), 5% sodium sulfate (20 mL), water (mL) and brine (20
mL). The organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue is kept at rt overnight to yield
4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-nitro-indol-1-yl)-amide (730 mg, 44%) as a solid. MS: 392 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sup.6): .delta. 2.78 (s, 3H), 6.88 (d,
H), 7.38-7.53 (m, H), 7.57-7.76 (m, 2H), 7.81 (d, H), 8.06-8.32 (m,
2H), 8.34 (d, H), 8.65 (d, H), 9.27 (s, 2H).
Example 205
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide
##STR00211##
[1129] A solution of
4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-nitro-indol-1-yl)-amide (1.64 mmol) in MeOH (45 mL) and 10% Pd/C
(0.16 mmol) is hydrogenated in a 500 mL Parr bottle under 50 psi at
rt overnight. Pd/C is filtered off. The filtrate is concentrated to
afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide (545 mg, 92%) as a solid. MS: 362 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 3.84 (s, H), 6.37 (d,
H), 6.81 (dd, H), 7.01 (d, H), 7.16-7.36 (m, 3H), 7.55 (m, H), 8.23
(d, H), 8.36 (d, H), 9.50 (s, H).
Example 206
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-(dimethanesulfonyl)-amino-indol-1-yl]-amide
##STR00212##
[1131] A mixture of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide (0.43 mmol) and methanesulfonyl chloride
(0.52 mmol) in anhydrous DCM (10 mL) is stirred at 0.degree. C. and
triethylamine (1.29 mmol) is added. The reaction mixture is stirred
at 0.degree. C. for 1 h, and then warmed to rt and stirred for 30
minutes. DCM is added (20 mL), and the mixture is washed with 4%
HCl (15 mL), water (10 mL) and brine (15 mL). The organic layer is
dried (Na.sub.2SO.sub.4), filtered and concentrated. The residue is
purified by chromatography using silica gel eluting with 0-60%
EtOAC in DCM to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-(dimethanesulfonyl)-amino-indol-1-yl]-amide (85 mg, 38%) as a
solid. MS: 518 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
2.75 (s, 3H), 2.90 (s, 3H), 3.66 (s, 3H), 6.51 (s, H), 7.04-7.53
(m, 6H), 8.03 (d, H), 8.12 (d, H), 8.60 (s, H).
Example 207
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-benzoylamino-indol-1-yl)-amide
##STR00213##
[1133] A solution of benzoyl chloride (0.85 mmol) in anhydrous DCM
(2 mL) is added drop-wise to a solution of
4-methyl-2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid
(5-amino-indol-1-yl)-amide (0.47 mmol) and triethylamine (1.41
mmol) in anhydrous DCM (16 mL) and the mixture is stirred at rt
overnight. The reaction mixture is concentrated in vacuo. The
residue is dissolved in EtOAc (25 mL), and washed with water
(2.times.20 mL) and brine (10 mL). The organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue is
triturated with EtOAc to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-benzoylamino-indol-1-yl)-amide (95 mg, 43%) as a solid. MS: 466
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sup.6): .delta. 2.99 (s, 3H),
6.72 (d, H), 7.38-7.48 (m, H), 7.48-7.80 (m, 6H), 7.83-8.016 (m,
3H), 8.07-8.20 (m, H), 8.23-8.35 (m, 2H), 9.24 (s, H), 10.25 (br,
H).
Example 208
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-indol-1-yl]-amide
dichlorochloride
##STR00214##
[1135] Step 1: A mixture of 5-fluoroindole (6.65 g, 49.2 mmol) and
4-piperidone hydrate hydrochloride (18.9 g, 123 mmol) in methanol
solution of 2 N KOH (90 mL) is refluxed for 6 h. After cooling to
rt, water (150 mL) is added and stirred at rt for 30 minutes. The
resulting precipitate is filtered, washed with water (10 mL) and
ether (15 mL), and dried in vacuo to afford
5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-indole (6.34 g, 60%).
MS: 217 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.40 (br,
H), 7.57 (dd, H), 7.24-7.37 (m, H), 7.23 (s, H), 6.98 (t, H), 6.20
(s, H), 3.62 (m, 2H), 3.16 (m, 2H), 2.50 (s, 2H).
[1136] Step 2: A solution of di-tert-butyl dicarbonate (504 mg,
2.31 mmol) in DCM (10 mL) is added to a stirred solution of
5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-indole (500 mg, 2.31
mmol) in DCM (20 mL) at rt and stirred at rt overnight. The
reaction mixture is concentrated in vacuo to afford
4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (730 mg). MS: 317 (M+H); .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 8.17 (br, H), 7.56 (d, H), 7.31 (m, H),
7.26 (s, H), 6.99 (t, H), 6.13 (s, H), 4.17 (m, 2H), 3.70 (m, 2H),
2.57 (s, 2H), 1.54 (s, 9H).
[1137] Step 3: A solution of
4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (730 mg, 2.31 mmol) in anhydrous DMF is added
slowly to a stirred solution of 60% NaH (1108 mg, 27.72 mmol) in
anhydrous DMF (20 mL) at 0.degree. C. under N.sub.2 and stirred at
rt for an hour. HOSA (1305 mg, 11.55 mmol) is added portion-wise at
0.degree. C., stirred at 0.degree. C. for 5 hours, poured into
ice/water (350 mL) and extracted with ether (3.times.35 mL). The
combined organic extract is washed with water (2.times.20 mL) and
brine (20 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo. The residue is washed with heptane (3.times.5 mL) to
afford
4-(1-Amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (715 mg, 94%) as a solid. MS: 332 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.52 (d, H), 7.36 (m,
H), 7.20 (s, H), 7.04 (t, H), 6.06 (s, H), 4.78 (s, 2H), 4.15 (m,
2H), 3.69 (t, 2H), 2.54 (s, 2H), 1.55 (s, 9H).
[1138] Step 4: Triethylamine (2.6 mmol) is added to a stirred
solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(1.30 mmol) and iso-butyl chloroformate (1.95 mmol) in anhydrous
DCM (20 mL) at rt under N.sub.2 and stirred at rt for 2 h. The
reaction mixture is concentrated in vacuo. The residue is dried in
vacuo and THF (30 mL) is added. The mixture is filtered and the
filtrate is concentrated to afford
iso-butyl-[1-(4-methyl-2-pyridin-2-yl-pyrimidin-5-yl]l-carbonate
(350 mg, 85%).
[1139] Step 5: Sodium bis(trimethylsilyl)amide (2 N) in THF (0.83
mL) is added to a stirred solution of
4-(1-amino-5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid tert-butyl ester (367 mg, 1.11 mmol) in anhydrous DMF (20 mL)
at rt under N.sub.2, then stirred at rt for 15 min. A solution of
iso-butyl-[1-(4-methyl-2-pyridin-2-yl-pyrimidin-5-yl]]-carbonate
(350 mg, 1.11 mmol) in anhydrous DMF (5 mL) is added slowly at rt
and stirred at 60.degree. C. for 18 hours under N.sub.2. DMF is
evaporated off. The residue is dissolved in EtOAc (60 mL), washed
with water (3.times.20 mL) and brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 0-20% MeOH in
DCM to afford
4-[5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester (158 mg, 28%).
[1140] Step 6: A solution of
4-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H--
indol-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester (158 mg) in DCM (15 ml) is bubbled with HCl gas for 10 min at
rt, then stirred at rt for 18 h. DCM is evaporated off and the
residue is triturated with MeOH (2 mL). The solid is collected by
filtration and dried to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-indol-1-yl]-amide
dichlorochloride (81 mg, 54%). MS: 429 (M+H); .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta.=2.89 (m, 2H), 2.96 (s, 3H), 3.53 (t, 2H), 3.94
(m, H), 6.27 (s, H), 7.12 (t, H), 7.46 (q, H), 7.59-7.71 (m, H),
8.28 (t, H), 8.85 (t, H), 8.99 (d, H), 9.15 (d, H), 9.41 (s,
H).
Example 209
2-Pyridin-2-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00215##
[1142] A solution of
2-pyridin-2-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid (219
mg, 0.81 mmol), 5-fluoro-3-methyl-indol-1-ylamine (0.98 mmol),
DIPEA (158 mg, 1.23 mmol) and HATU (1.06 mmol) in anhydrous DMF (8
mL) is stirred at 80.degree. C. overnight. The reaction mixture is
diluted with EtOAc (40 mL) and washed with water (4.times.20 mL)
and brine (20 mL).
[1143] The organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 1%-50% EtOAc in DCM. The collected
product is recrystallized from DCM to afford
2-pyridin-2-yl-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (105 mg, 31%) as a solid. MS:
416 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.=2.32 (s, 3H),
7.04 (t, H), 7.16 (s, H), 7.25 (dd, H), 7.34 (q, H), 7.67 (dd, H),
8.11 (t, H), 8.70 (d, H), 8.82 (d, H), 9.57 (s, H). IC.sub.50=8
nM.
Example 210
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide
##STR00216##
[1145] A mixture of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-2,3-dihydro-indol-1-yl)-amide (246 mg, 0.68 mmol) and
MnO.sub.2 (296 mg, 3.4 mmol) in DCM (10 mL) is stirred at rt for
1.5 h. The reaction mixture is filtered and the filtrate is
concentrated in vacuo. The residue is triturated with ether to
afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide (158, 65%). MS: 361 (M+H); .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 2.39 (s, 3H), 2.83 (s, 3H), 6.36 (s,
H), 7.10-7.29 (m, 3H), 7.44-7.62 (m, H), 8.17 (s, H), 8.25 (d, H),
8.35 (d, H), 8.97 (s, H).
Example 211
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide
##STR00217##
[1147] Step 1: LiAlH.sub.4 (14.7 mmol, 1 M solution in THF) is
added to a solution of 6-fluoro-4H-benzo[1,4]oxazin-3-one (1.23 g,
7.35 mmol) in THF at rt and heated to reflux for 2 hrs. The
reaction mixture is quenched with a few drops of water followed by
slow addition of ethyl acetate (10 mL). The solid is filtered off,
and washed with EtOAc. The filtrate is concentrated in vacuo to
afford 6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g). MS: 154
(M+H).
[1148] Step 2: Isoamyl nitrite is added to a solution of
6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine (1 g) in DCM (15 mL) and
heated to reflux overnight. The reaction mixture is concentrated in
vacuo and the residue is purified by silica gel chromatography
eluting with 10% EtOAc in heptane to give
6-Fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine (0.83 g).
[1149] Step 3: LiAlH.sub.4 in THF (1 M, 6.58 mL) is added to a
solution of 6-fluoro-4-nitroso-3,4-dihydro-2H-benzo[1,4]oxazine
(0.8 g) in THF (10 mL) at 0.degree. C. and then stirred at rt
overnight. The reaction mixture is quenched with a few drops of
water followed by addition of EtOAc (10 mL). The solid is filtered
off and washed with EtOAc (15 mL). The filtrate is concentrated in
vacuo and the residue is purified by silica gel column
chromatography eluting with 15% EtOAc in heptane to afford
6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (0.44 mg).
[1150] Step 4: DIPEA (174 .mu.L) is added to a mixture of
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (218 mg), HATU
(380 mg) and 6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (220
mg) in DMF (15 mL) and then heated at 80.degree. C. overnight. The
reaction mixture is concentrated in vacuo and the residue is
purified by silica gel column chromatography eluting with 30% EtOAc
in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic
acid (6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide (81 mg). MS:
369 (M+H); .sup.1H NMR (300 MHz, DMSO-D.sub.6): .delta. 11.05 (s,
1H), 9.35 (s, 2H), 8.32 (dd, 1H), 8.18 (dd, 1H), 7.65 (m, 1H), 7.5
(m, 1H), 6.8-6.7 (m, 2H), 6.52-6.45 (m, 1H), 4.36-4.33 (m, 2H),
3.65 (m, 2H). IC.sub.50=12 nM.
Example 212
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide
##STR00218##
[1152] Following procedures similar to those of step 4 in Example
211, but substituting 2-phenyl-pyrimidine-5-carboxylic acid for
2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, there is prepared
2-phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide as solid. MS: 351
(M+H); .sup.1H NMR (300 MHz, DMSO-D.sub.6): .delta. 11.03 (s, 1H),
9.33 (s, 2H), 8.49-8.46 (m, 2H), 7.61-7.55 (m, 3H), 6.8-6.7 (m,
2H), 6.52-6.45 (m, 1H), 4.36-4.33 (m, 2H), 3.65-3.25 (m, 2H).
IC.sub.50=21 nM.
Example 213
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide
##STR00219##
[1154] Step 1: A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (3
g, 12.6 mmol) in DCM (40 mL) is treated with TFAA (2.1 mL, 15.1
mmol) and pyridine (1.2 mL, 15.1 mmol), and stirred at rt for 2 h.
The mixture is diluted with H.sub.2O (150 mL), and extracted with
DCM (3.times.150 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is diluted with MeCN (40 mL), treated with trans-crotyl bromide (2
mL, 18.9 mmol) and K.sub.2CO.sub.3 (3.5 g, 25.2 mmol), and heated
at reflux for 2 h. The mixture is cooled, filtered through a pad of
Celite and concentrated. The residue is purified by silica gel
chromatography eluting with 5%-30% EtOAc in heptane to afford
N-but-2-enyl-2,2,2-trifluoro-N-(5-fluoro-3-iodo-pyridin-2-yl)-acetamide
(2.5 g, 51%). MS: 389 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 8.36 (m, 1H), 7.98 (s, 1H), 5.55 (m, 2H), 4.62 (m, 1H),
3.96 (m, 1H), 1.61 (m, 3H).
[1155] Step 2: A solution of
N-but-2-enyl-2,2,2-trifluoro-N-(5-fluoro-3-iodo-pyridin-2-yl)-acetamide
(2.57 g, 6.5 mmol) in DMF (10 mL) is treated with n-Bu.sub.4NCl (2
g, 7.15 mmol), Pd(OAc).sub.2 (59 mg, 0.26 mmol), and stirred at
100.degree. C. for 2 h. The mixture is cooled to rt, diluted with
EtOAc (50 mL), filtered through a pad of silica gel, and washed
with 1 M HCl (50 mL). The organic layer is separated, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 25%-70% EtOAc
in heptane to afford 3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine
(0.75 g, 70%). MS: 165 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 9.62 (s, NH, 1H), 8.17 (m, 1H), 7.60 (m, 1H), 7.16 (s, 1H),
2.74 (q, 2H), 1.31 (t, 3H).
[1156] Step 3: A suspension of NaH (2.7 g, 68 mmol, 60% in mineral
oil) in DMF (20 mL) at 0.degree. C. is treated with
3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (745 mg, 4.5 mmol) and
stirred at 0.degree. C. for 1 h. The mixture is treated with HOSA
(2.5 g, 22.5 mmol) portion wise and warmed to rt over 2 h. The
mixture is then poured over ice, filtered through a pad of Celite,
and extracted with EtOAc (3.times.50 mL). The combined organic
layer is dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue is purified by silica gel chromatography eluting
with 30% -50% EtOAc in heptane to afford
3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (685 mg, 84%). MS:
180 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.16 (s, 1H),
7.56 (m, 1H), 7.14 (s, 1H), 4.93 (s, NH.sub.2, 2H), 2.697 (q, 2H),
1.28 (t, 3H).
[1157] Step 4: A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (490 mg, 2.28
mmol) and 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (340 mg,
1.9 mmol) in DMF (6 mL) is stirred at 40.degree. C. for 1 h. The
mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at
40.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (427 mg, 60%).
MS: 377 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.94
(s, NH, 1H), 9.14 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.30 (s,
1H), 8.03 (m, 2H), 7.61 (m, 2H), 2.81 (s, 3H), 2.75 (q, 2H), 1.29
(t, 3H).
Example 214
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide
##STR00220##
[1159] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (509 mg, 2.28
mmol) and 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (340 mg,
1.9 mmol) in DMF (6 mL) is stirred at 40.degree. C. for 1 h. The
mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at
40.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-ethyl-5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (481 mg, 66%).
MS: 383 (M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.95
(s, NH, 1H), 9.10 (s, 1H), 8.29 (s, 1H), 8.14 (d, 1H), 8.08 (d,
1H), 8.00 (m, 1H), 7.57 (s, 1H), 2.79 (s, 3H), 2.75 (q, 2H), 1.29
(t, 3H).
Example 215
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide
##STR00221##
[1161] Step 1: A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (4
g, 16.8 mmol) in THF (50 mL) and trimethylsilylacetylene (4.7 mL,
33.6 mmol) is treated with PdCl.sub.2(PPh.sub.3).sub.4 (353 mg, 0.5
mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 mL, 50.4 mmol)
and stirred at rt for 2 h. The mixture is filtered through Celite
and concentrated. The residue is purified by silica gel
chromatography eluting with 10%-35% EtOAc in heptane to afford
5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.3 g, 94%).
MS: 209 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.90 (d,
1H), 7.30 (m, 1H), 4.89 (s, NH.sub.2, 2H), 0.25 (s, 9H).
[1162] Step 2: A solution of
5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.2 g, 15.4
mmol) in MeOH (77 mL) and K.sub.2CO.sub.3 (11 g, 7.7 mmol) is
stirred at rt for 0.5 h. The mixture is filtered through Celite and
concentrated. The residue is purified by silica gel chromatography
eluting with 15%-55% EtOAc in heptane to afford
3-ethynyl-5-fluoro-pyridin-2-ylamine (1.55 g, 74%). MS: 137 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.94 (d, 1H), 7.35 (m,
1H), 4.91 (s, NH.sub.2, 2H), 3.44 (s, 1H).
[1163] Step 3: A solution of 3-ethynyl-5-fluoro-pyridin-2-ylamine
(1.25 g, 9.2 mmol) in DMF (20 mL) is treated with
(Rh(cod).sub.2Cl).sub.2 (23 mg, 0.023 mmol) and
tris-(4-fluoro-phenyl)-phosphane (115 mg, 0.368 mmol) and stirred
at 85.degree. C. for 0.5 h. The mixture is then poured over brine
(50 mL), and extracted with EtOAc (3.times.50 mL). The combined
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 35%-75% EtOAc in heptane to afford
5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.05 g, 84%). MS: 137 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.15 (s, NH, 1H), 7.99
(s, 1H), 7.44 (d, 1H), 7.18 (s, 1H), 6.28 (s, 1H).
[1164] Step 4: A suspension of NaH (4.4 g, 110 mmol, 60% in mineral
oil) in DMF (37 mL) at 0.degree. C. is treated with
5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 7.4 mmol) and stirred at
0.degree. C. for 1 h. The mixture is treated with HOSA (4.2 g, 37
mmol) portion wise and warmed to rt over 2 h. The mixture is then
poured over ice, filtered through a pad of Celite, and extracted
with EtOAc (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 30%-70% EtOAc
in heptane to afford 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (980
mg, 88%). MS: 152 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.20 (s, 1H), 7.60 (m, 1H), 7.42 (m, 1H), 6.36 (s, 1H), 5.01 (s,
NH.sub.2, 2H).
[1165] Step 5: A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (529 mg,
2.28 mmol) and 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (288 mg,
1.9 mmol) in DMF (6 mL) is stirred at 40.degree. C. for 1 h. The
mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at
40.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (475 mg, 68%). MS: 366
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.12 (s, 1H),
8.30 (m, 2H), 8.18 (d, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 7.59 (m,
1H), 7.44 (m, 1H), 6.59 (d, 1H), 2.80 (s, 3H).
Example 216
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide
##STR00222##
[1167] A solution of
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (440 mg, 2.28
mmol) and 5-fluoro-pyrrolo[2,3-b]pyridin-1-ylamine (288 mg, 1.9
mmol) in DMF (6 mL) is stirred at 40.degree. C. for 1 h. The
mixture is treated with DMTMM (524 mg, 1.9 mmol) and stirred at
40.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-pyrrolo[2,3-b]pyridin-1-yl)-amide (343 mg, 52%). MS: 349
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.17 (s, 1H),
8.81 (d, 1H), 8.53 (d, 1H), 8.27 (s, 1H), 8.01 (m, 1H), 7.90 (m,
1H), 7.77 (d, 1H), 7.57 (m, 1H), 6.60 (d. 1H), 2.84 (s, 3H).
Example 217
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide
##STR00223##
[1169] Step 1: A solution of 4-fluoro-2-iodoaniline (2 g, 8.4 mmol)
in THF (15 mL) and cyclopropylacetylene (1.4 mL, 16.9 mmol) is
treated with PdCl.sub.2(PPh.sub.3).sub.4 (177 mg, 0.25 mmol), CuI
(48 mg, 0.25 mmol) and triethylamine (3.5 mL, 25.2 mmol) and
stirred at rt for 2 h. The mixture is filtered through Celite and
concentrated. The residue is purified by silica gel chromatography
eluting with 0%-35% EtOAc in heptane to afford
2-cyclopropylethynyl-4-fluoro-phenylamine (1.1 g, 74%). MS: 176
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 6.93 (m, 1H),
6.81 (m, 1H), 6.59 (m, 1H), 4.00 (s, NH.sub.2, 2H), 1.49 (m, 1H),
0.82 (m, 4H).
[1170] Step 2: A solution of
2-cyclopropylethynyl-4-fluoro-phenylamine (0.80 g, 4.5 mmol) in
PhMe (16 mL) is treated with InBr.sub.3 (80 mg, 0.23 mmol) and
stirred at 110.degree. C. for 0.5 h. The mixture is then poured
over brine (20 mL), and extracted with EtOAc (3.times.20 mL). The
combined organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue is purified by silica gel
chromatography eluting with 0%-25% EtOAc in heptane to afford
2-cyclopropyl-5-fluoro-1H-indole (610 mg, 78%). MS: 176 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.88 (s, NH, 1H), 7.12
(m, 2H), 6.83 (m, 1H), 6.09 (s, 1H), 1.90 (m, 1H), 0.95 (m, 2H),
0.77 (m, 2H).
[1171] Step 3: A suspension of NaH (1.9 g, 47 mmol, 60% in mineral
oil) in DMF (20 mL) at 0.degree. C. is treated with
2-cyclopropyl-5-fluoro-1H-indole (550 mg, 3.14 mmol) and stirred at
0.degree. C. for 1 h. The mixture is treated with HOSA (1.8 g, 15.7
mmol) portion wise and warmed to rt over 2 h. The mixture is then
poured over ice, filtered through a pad of Celite, and extracted
with EtOAc (3.times.50 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
is purified by silica gel chromatography eluting with 5%-35% EtOAc
in heptane to afford 2-cyclopropyl-5-fluoro-indol-1-ylamine (420
mg, 70%). MS: 191 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.30 (m, 1H), 7.11 (m, 1H), 6.92 (m, 1H), 5.90 (s, 1H), 4.57 (s,
NH.sub.2, 2H), 2.07 (m, 1H), 1.02 (m, 2H), 0.75 (m, 2H).
[1172] Step 4: A solution of
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid (184 mg, 0.85 mmol)
and 2-cyclopropyl-5-fluoro-indol-1-ylamine (135 mg, 0.71 mmol) in
DMF (3 mL) is stirred at 40.degree. C. for 1 h. The mixture is
treated with DMTMM (235 mg, 0.71 mmol) and stirred at 40.degree. C.
for 1 h. The mixture is diluted with saturated aqueous
Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The precipitate is
collected by filtration and dried in vacuo to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide (35 mg, 13%). MS: 389
(M+H); .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 11.93 (s, NH,
1H), 9.31 (s, 1H), 9.06 (d, 2H), 7.70 (m, 1H), 7.42 (m, 1H), 7.26
(m, 1H), 6.97 (m, 1H), 6.16 (s, 1H), 2.79 (s, 3H), 1.97 (m, 1H),
1.01 (m, 2H), 0.74 (m, 2H).
Example 218
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide
##STR00224##
[1174] A solution of
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (188 mg, 0.85
mmol) and 2-cyclopropyl-5-fluoro-indol-1-ylamine (135 mg, 0.71
mmol) in DMF (3 mL) is stirred at 40.degree. C. for 1 h. The
mixture is treated with DMTMM (235 mg, 0.71 mmol) and stirred at
40.degree. C. for 1 h. The mixture is diluted with saturated
aqueous Na.sub.2CO.sub.3 (5 mL) and stirred for 5 min. The
precipitate is collected by filtration and dried in vacuo to afford
4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(2-cyclopropyl-5-fluoro-indol-1-yl)-amide (60 mg). MS: 394 (M+H);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.26 (s, 1H), 8.15 (d,
1H), 8.08 (d, 1H), 7.43 (m, 1H), 7.24 (m, 1H), 6.97 (m, 1H), 6.18
(s, 1H), 2.77 (s, 3H), 1.95 (m, 1H), 1.01 (m, 2H), 0.73 (m,
2H).
Example 219
2-Pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxyl-indol-1-yl)-amide
##STR00225##
[1176] A solution of
2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (496 mg,
2.30 mmol) and 5-methoxy-indol-1-ylamine (0.98 mmol) in anhydrous
DMF (10 mL) is stirred at 50.degree. C. for 30 min. DMTMM (555 mg,
2.01 mmol) is added and stirred at 50.degree. C. for an hour. DMF
is evaporated off. The residue is mixed with water (40 mL) and
stirred at rt for 20 minutes. The solid is collected by filtration,
washed with water (3.times.5 mL) and dried in vacuum to afford
2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxyl-indol-1-yl)-amide (410 mg) as a solid. MS: 361 (M+H);
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.93 (s, 3H), 4.84 (s,
3H), 7.04 (t, H), 6.50 (d, H), 6.92 (d, H), 7.14 (s, H), 7.26-7.37
(m, 2H), 7.72 (t, H), 9.09 (d, 2H), 9.27 (s, H).
Example 220
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo [32-b]pyridin-1-yl)-amide
##STR00226##
[1178] Step 1: Bromine (1.96 g, 12.2 mmol) is added to a mixture of
2-fluoro-5-aminopyridine (1.37 g, 12.2 mmol) and sodium acetate (2
mg, 24.4 mmol) in acetic acid (30 mL) and stirred at rt for 4
hours. Acetic acid is evaporated off in vacuo. The residue is
dissolved in EtOAc (50 mL), washed with saturated aqueous
Na.sub.2CO.sub.3 (10 mL), water (20 mL) and brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo to afford
2-bromo-3-amino-6-fluoropyridine (2.1 g) as a solid. MS: 190 (M+H);
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 4.04 (br, 2H), 6.77 (dd,
H), 7.17 (dd, H).
[1179] Step 2: TFAA (8.31 g, 39.57 mmol) is added drop-wise to a
stirred solution of 2-bromo-3-amino-6-fluoropyridine (6.30 g, 33.0
mmol) and pyridine (3.91 g, 49.46 mmol) in DCM (80 mL) at rt, and
stirred at rt for an hour. Water (40 mL) is added. The organic
layer is separated, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo to afford
N-(2-bromo-6-fluoropyridin-3-yl)-2,2,2-trifluoro-acetamide (9.37 g,
>99%) as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
7.06 (m, H), 8.40 (br, N--H), 9.75 (dd, H).
[1180] Step 3: A solution of
N-(2-bromo-6-fluoropyridin-3-yl)-2,2,2-trifluoro-acetamide (9.16 g,
31.9 mmol), allyl bromide (6.18 g, 47.9 mmol) and sodium carbonate
(8.82 g, 63.8 mmol) in CH.sub.3CN (80 mL) is stirred at 80.degree.
C. for 2 h. The reaction mixture is concentrated in vacuo and the
residue is purified by silica gel chromatography eluting with 0-60%
DCM in heptane to afford
N-allyl-N-(2-bromo-6-fluoro-pyridin-3-yl)-2,2,2-trifluoro-acetamide
(9.05 g) as an oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.68
(q, H), 5.01 (q, H), 5.17 (d, H), 5.29 (d, H), 6.85 (m, H), 7.00
(dd, H), 7.64 (t, H).
[1181] Step 4: A solution of
N-allyl-N-(2-bromo-6-fluoro-pyridin-3-yl)-2,2,2-trifluoro-acetamide
(3.41 g, 10.43 mmol), palladium acetate (94 mg, 0.42 mmol),
tetra(n-butylammonium) chloride (3.19 g, 11.47 mmol) and
triethylamine (2.37 g, 23.4 mmol) in anhydrous DMF (20 mL) is
stirred at 10.degree. C. under N.sub.2 for an hour. DMF is
evaporated off and the residue is mixed with water (12 mL) and
stirred at rt for an hour. EtOAc (15 mL) is added and stirred at rt
overnight. The organic layer is separated and the aqueous layer is
extracted with EtOAc (35 mL). The combined organic layer is dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with
10-60% EtOAc in heptane to afford
5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine (1.5 g) as a solid. MS:
151 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.38 (s, 3H),
6.77 (d, H), 7.28 (s, H), 7.74 (dd, H).
[1182] Step 5: A solution of
5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine (10.7 mmol) in
anhydrous DMF (15 mL) is added drop-wise to a stirred solution of
NaH (60%, 160 mmol) in anhydrous DMF (25 mL) under N.sub.2 at
0.degree. C. for 20 min and stirred at 0.degree. C. under N.sub.2
for 30 minutes. HOSA (53.5 mmol) is added portion-wise for 30
minutes at 0.degree. C., and stirred at 0.degree. C. for 1.5 hours.
After quenching with ice-water (400 mL), the mixture is extracted
with ether (3.times.60 mL). The combined organic layer is washed
with water (2.times.30 mL) and brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel column chromatography eluting
with 0-60% EtOAc in heptane to afford
5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (570 mg). MS: 166
(M+H); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.32 (s, 3H), 4.82
(br, 2N--H), 6.76 (d, H), 7.17 (s, H), 7.77 (dd, H).
[1183] Step 6: A solution of
2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.41 mmol),
5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.41 mmol),
DIPEA (158 mg, 4.22 mmol) and HATU (1.69 mmol) in anhydrous DMF (8
mL) is stirred at 90.degree. C. for 16 hours. DMF is evaporated off
in vacuo. The residue is dissolved in EtOAc (40 mL), washed with
water (3.times.10 mL) and brine (10 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 1-20% MeOH in DCM to afford
4-methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (125 mg) as a
solid. MS: 364 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
2.31 (s, 3H), 2.87 (s, 3H), 6.87 (d, H), 7.50 (s, H), 7.66 (t, H),
7.96 (t, H), 9.04 (d, 2H), 9.27 (s, H).
Example 221
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo [3,2-b]pyridin-1-yl)-amide
##STR00227##
[1185] A solution of
2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.36 mmol),
5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.36 mmol),
DIPEA (158 mg, 4.07 mmol) and HATU (1.63 mmol) in anhydrous DMF (8
mL) is stirred at 90.degree. C. for 15 hours. DMF is evaporated in
vacuo. The residue is dissolved in EtOAc (40 mL), washed with water
(3.times.15 mL) and brine (10 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The residue is recrystallized
from EtOAc to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (285 mg) as a
solid. MS: 363 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
2.35 (s, 3H), 2.87 (s, 3H), 6.92 (d, H), 7.51 (s, H), 7.60 (t, H),
7.97 (t, H), 8.05 (t, H), 8.65 (d, H), 8.78 (d, H), 9.23 (s,
H).
Example 222
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00228##
[1187] A solution of
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34
mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.34
mmol), DIPEA (158 mg, 4.02 mmol) and HATU (1.60 mmol) in anhydrous
DMF (8 mL) is stirred at 90.degree. C. for 16 h. DMF is evaporated
off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed
with water (3.times.20 mL) and brine (10 mL). The organic layer is
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel chromatography eluting with 0-60%
EtOAc in heptane to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (340 mg) as a
solid. MS: 380 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
2.36 (s, 3H), 2.86 (s, 3H), 6.84 (d, H), 7.12-7.35 (m, 2H), 7.52
(q, H), 7.63 (t, H), 8.10-8.43 (m, 2H), 8.98 (br, N--H).
Example 223
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00229##
[1189] Step 1: Bromine (4.72 g, 29.5 mmol) is added to a mixture of
2-methoxy-5-aminopyridine (3.66 g, 29.5 mmol) and sodium acetate
(4.84 g, 7.32 mmol) in acetic acid (50 mL) and stirred at rt for 20
minutes. Acetic acid is evaporated off in vacuo. The residue is
dissolved in EtOAc (40 mL), and washed with water (40 mL),
saturated sodium carbonate aqueous solution (20 mL), water (20 mL)
and brine (20 mL). The organic layer is dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The residue is purified by
silica gel chromatography eluting with 0-40% EtOAc in heptane to
afford 2-bromo-3-amino-6-methoxypyridine (4.35 g) as an oil. MS:
202 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.89 (s, 3H),
6.60 (d, H), 7.07 (d, H).
[1190] Step 2: TFAA (5.15 g, 24.5 mmol) is added drop-wise to a
stirred solution of 2-bromo-3-amino-6-methoxypyridine (4.15 g, 20.5
mmol) and pyridine (1.94 g, 24.5 mmol) in DCM (60 mL) at rt and
stirred at rt for 2.5 h. Water (40 mL) is added. The organic layer
is separated, dried (Na.sub.2SO.sub.4), filtered, and concentrated
in vacuo to afford
N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.68
g) as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.96 (s,
H), 6.80 (s, H), 8.23 (br, N--H), 8.42 (d, H).
[1191] Step 3: A mixture of
N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide (5.52
g, 18.5 mmol), allyl bromide (3.57 g, 27.7 mmol) and sodium
carbonate (5.1 g, 11 mmol) in CH.sub.3CN (60 mL) is stirred at
80.degree. C. for 3 h. The mixture is filtered and the filtrate is
concentrated in vacuo. The residue is purified by silica gel column
chromatography eluting with 0-60% DCM in heptane to afford
N-allyl-N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide
(5.55 g) as an oil. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 3.66
(q, H), 4.00 (s, H), 5.95 (q, H), 5.08-5.30 (q, 2H), 5.75-5.94 (m,
H), 6.74 (d, H), 7.38 (d, H).
[1192] Step 4: A solution of
N-allyl-N-(2-bromo-6-methoxy-pyridin-3-yl)-2,2,2-trifluoro-acetamide
(5.54 g, 16.3 mmol), palladium acetate (147 mg, 0.65 mmol),
tetra(n-butylammonium) chloride (4.99 g, 17.9 mmol) and
triethylamine (3.72 g, 26.8 mmol) in anhydrous DMF (35 mL) is
stirred at 10.degree. C. under N.sub.2 for an hour. DMF is
evaporated off, and the residue is mixed with water (20 mL) and
stirred at rt overnight. EtOAc (50 mL) is added. The organic layer
is separated, dried (Na.sub.2SO.sub.4), filtered, and concentrated
in vacuo. The residue is purified by silica gel column
chromatography eluting with 30-70% EtOAc in heptane to afford
5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine (2.62 g) as a solid.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.38 (s, 3H), 4.05 (s,
3H), 6.62 (s, H), 7.12 (s, H), 7.54 (d, H), 7.94 (br, N--H).
[1193] Step 5: A solution of
5-methoxy-3-methyl-1H-pyrrolo[3,2-b]pyridine (17.3 mmol) in
anhydrous DMF (20 mL) is added drop-wise to a stirred solution of
NaH (60%, 260 mmol) in anhydrous DMF (35 mL) under N.sub.2 at
0.degree. C. for 40 min and then stirred at 0.degree. C. under
nitrogen for 30 minutes. HOSA is added portion-wise for 45 minutes
at 0.degree. C. and then stirred at 0.degree. C. for 2 hours. After
quenching with ice-water (500 mL), the reaction mixture is
extracted with ether (3.times.40 mL). The combined organic layer is
washed with water (20 mL) and brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel column chromatography eluting
with 5-60% EtOAc in heptane to afford
5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.73 g) as a
solid. MS: 178 (M+H); .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
2.34 (s, 3H), 4.04 (s, 3H), 4.75 (br, 2N--H), 6.63 (d, H), 7.04 (s,
H), 7.60 (d, H).
[1194] Step 6: A solution of
2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.69 mmol),
5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.69 mmol),
DIPEA (5.01 mmol) and HATU (2.03 mmol) in anhydrous DMF (8 mL) is
stirred at 90.degree. C. for 16 h. DMF is evaporated in vacuo. The
residue is dissolved in EtOAc (40 mL), and washed with water
(3.times.10 mL) and brine (10 mL). The organic layer is dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is purified by silica gel column chromatography eluting
with 0-15% MeOH in DCM to afford
4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (295 mg) as a
solid. MS: 375 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
2.40 (s, 3H), 2.84 (s, 3H), 4.02 (s, 3H), 6.70 (d, H), 7.13 (s, H),
7.41 (m, H), 7.50 (d, H), 7.85 (t, H), 8.51 (m, 2H), 8.78 (s, 2H),
10.57 (br, N--H).
Example 224
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide
##STR00230##
[1196] A solution of 2-(3-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid (1.13 mmol),
5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.13 mmol),
DIPEA (3.39 mmol) and HATU (1.36 mmol) in anhydrous DMF (8 mL) is
stirred at 90.degree. C. for 16 h. DMF is evaporated off in vacuo.
The residue is dissolved in EtOAc (45 mL), and washed with water
(3.times.20 mL) and brine (10 mL). The organic layer is dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue is is triturated with DCM to afford
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (265 mg) as a
solid. MS: 392 (M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
2.33 (s, 3H), 2.79 (s, 3H), 3.97 (s, 3H), 6.67 (d, H), 7.20-7.60
(m, 2H), 7.53 (m, H), 7.64 (d, H), 8.17 (t, H), 8.34 (t, 2H),
9.05-9.20 (d, H).
Example 225
4-Methyl-2-(1-oxy-pyridin-2-yl)-pyrimidin-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00231##
[1198] Step 1: A solution of 2-cyanopyridine (1.67 g, 16 mmol), 30%
H.sub.2O.sub.2 (3.2 mL) and methyltrioxorhenium (0.2 g, 0.8 mmol)
in DCM (6.4 mL) is stirred at rt overnight. The reaction mixture is
concentrated in vacuo and the residue is purified by silica gel
chromatography eluting with 3-10% MeOH in DCM to afford
1-oxy-pyridine-2-carbonitrile (0.69 g) as a solid. .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 7.34 (t, H), 7.49 (t, H), 7.67 (d, H),
8.30 (d, H).
[1199] Step 2: A solution of 1-oxy-pyridine-2-carbonitrile (532 mg,
4.43 mmol) and sodium methoxide (0.5 M in MeOH, 0.88 mL) in MeOH
(1.8 mL) is stirred at rt overnight. Ammonium chloride (261 mg.
4.87 mmol) is added and stirred at 56.degree. C. for an hour, and
then 7 N ammonia in MeOH (1.5 mL) is added. The reaction mixture is
sealed in a tube and stirred at 40.degree. C. for an hour, and then
cooled to 0.degree. C. Sodium methoxide is added (0.5 M in MeOH,
8.86 mL). The mixture is filtered and the filtrate is concentrated
in vacuo. The residue is recrystallized from ethanol to afford
1-oxy-pyridine-2-carboxamidine (370 mg) as a solid. .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.52-7.68 (m, 2H), 7.96 (dd, H),
8.35 (d, H).
[1200] Step 3: A solution of 1-oxy-pyridine-2-carboxamidine (366
mg, 2.67 mmol) and N,N-dimethylaminomethylene acetoacetate (495 mg,
2.76 mmol) in ethanol (3 mL) and DMF (3 ml) is stirred at
90.degree. C. for 16 hours. The reaction mixture is concentrated in
vacuo and the residue is purified by silica gel column
chromatography eluting with 2.5% MeOH in DCM to afford
4-methyl-2-(1-oxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid ethyl
ester (127 mg) as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 1.47 (t, 3H), 2.95 (s, 3H), 4.50 (q, 2H), 7.39 (m, H), 7.70
(q, H), 8.36 (q, H), 9.37 (s, H).
[1201] Step 4: A solution of
4-methyl-2-(-loxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid ethyl
ester (123 mg, 0.48 mmol) and sodium hydroxide (123 mg, 3.07 mmol)
in a mixture of MeOH/THF/H.sub.2O (3 mL, 1:1:1) is stirred at
65.degree. C. for 5 minutes, and then stirred at rt overnight (16
hours). 1 N HCl aqueous solution (3.07 mL) is added. The resulting
solution is concentrated to afford
4-methyl-2-(1-oxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid and
sodium chloride (313 mg), which is used in the next step without
further purification.
[1202] Step 5: A solution of
4-methyl-2-(1-oxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid and
sodium chloride (313 mg), 3-methyl-5-fluoro-indol-1-ylamine (78 mg,
0.48 mmol), DIEA (92 mg, 0.71 mmol) and HATU (217 mg, 0.57 mmol) in
anhydrous DMF (2.4 mL) is stirred at 150.degree. C. for 1 hour. DMF
is vaporated off. The residue is purified by silica gel column
chromatography eluting with 2.5-10% MeOH in DCM to afford
4-methyl-2-(1-oxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide (169 mg) as a solid. MS: 378
(M+H); .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.=1.52 (s, 3H),
2.84 (s, 3H), 7.02 (t, H), 7.18 (s, H), 7.25 (d, H), 7.35 (q, H),
7.62-7.80 (m, 2H), 7.85 (dd, H), 8.48 (d, H), 9.21 (s, H).
IC.sub.50=851.5 nM.
Example 226
2-(3-Difluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00232##
[1204] Following procedures similar to those of Example 158, step
4, but substituting
2-(3-difluoromethyl-phenyl)-2-yl-pyrimidine-5-carboxylic acid for
2-thiazol-2-yl-pyrimidine-5-carboxylic acid, there is prepared
2-(3-difluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide. MS: 397 (M+H); .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 2.27 (s, 3H), 7.04 (dt, 1H), 7.13
(d, 1H), 7.32 (s, 1H), 7.34-7.44 (m, 2H), 7.73-7.85 (m, 2H), 8.66
(d, 1H), 8.69 (s, 1H), 9.45 (s, 2H). IC.sub.50=17 nM.
Example 227
2-(3-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide
##STR00233##
[1206] Following procedures similar to those of Example 158, step
4, but substituting
2-(3-trifluoromethyl-phenyl)-2-yl-pyrimidine-5-carboxylic acid for
2-thiazol-2-yl-pyrimidine-5-carboxylic acid, there is prepared
2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide. MS: 415 (M+H). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 2.27 (s, 3H), 7.04 (dt, 1H), 7.33
(s, 1H), 7.34-7.44 (m, 2H), 7.86 (t, 1H), 8.00-8.02 (m, 1H),
8.75-8.79 (m, 2H), 9.47 (s, 2H). IC.sub.50=262 nM.
[1207] Following procedures similar to those described in the above
examples, the following compounds are made: [1208]
2-Phenyl-pyrimidine-5-carboxylic acid
(4-benzyl-piperazin-1-yl)-amide, [1209]
2-Phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide, [1210]
2-Phenyl-pyrimidine-5-carboxylic acid
(4-methanesulfonyl-piperazin-1-yl)-amide, [1211]
2-(2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [1212] 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-2-carbonyl)-piperazin-1-yl]-amide, [1213]
2-Phenyl-pyrimidine-5-carboxylic acid
[4-(1-methyl-1H-imidazole-4-carbonyl)-piperazin-1-yl]-amide, [1214]
4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic
acid tert-butyl ester, [1215] 2-Phenyl-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide, [1216]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
[4-(4-trifluoromethyl-phenoxy)-piperidin-1-yl]-amide, [1217]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
morpholin-4-ylamide, [1218] 2-Phenyl-pyrimidine-5-carboxylic acid
indol-1-ylamide, [1219] 2-Phenyl-pyrimidine-5-carboxylic acid
(4-methoxy-piperidin-1-yl)-amide, [1220]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-indol-1-yl)-amide, [1221]
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide, [1222]
2-Phenyl-pyrimidine-5-carboxylic acid
(6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-yl)-amide, [1223]
1-{[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-3-(2-morph-
olin-4-yl-ethyl)-1H-indole-6-carboxylic acid methyl ester, [1224]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide, [1225]
N-methyl-N-(5-fluoro)-indol-3-ylsulfonyl
N'-[2-(3-fluoro)-phenyl-pyrimidine-5-carbonyl]-hydrazide, [1226]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
[5-fluoro-3-(tetrahydro-pyran-4-yl)-indol-1-yl]-amide, [1227]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [1228]
4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1229]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [1230]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1231]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1232]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1233]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1234]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1235]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [1236]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1237]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1238]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1239]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1240]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [1241]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1242]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1243]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1244]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [1245]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1246]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1247]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1248]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1249]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [1250]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1251]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [1252]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1253]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1254]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl -pyrrolo[2,3-c]pyridin-1-yl)-amide, [1255]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1256]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [1257]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1258]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1259]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1260]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-b]pyridin-1-ylamide, [1261]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1262]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1263]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1264]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1265]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1266]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[2,3-c]pyridin-1-ylamide, [1267]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1268]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1269]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1270]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1271]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
pyrrolo[3,2-c]pyridin-1-ylamide, [1272]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-isopropyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1273]
4-Methyl-2-(4-chloro-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1274]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1275]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [1276]
2-(4-Methyl-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-fluoro-3-methyl-indol-1-yl)-amide, [1277]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(2-methyl-3-oxo-2,3-dihydro-indazol-1-yl)amide, [1278]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid(5-fluoro-indol-1-yl)amide)amide, [1279]
6-(4-Chloro-thiazol-2-yl)-2-methyl-N-pyrrolo[2,3-c]pyridin-1-yl-nicotinam-
ide, [1280] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic
acid(5-methyl-4-oxo-4,5-dihydro-pyrrolo[3,2-c]pyridin-1-yl)amide,
[1281] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid (5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1282]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1283]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1284]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1285]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1286] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1287] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1288] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1289] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1290] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1291] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1292] 4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1293] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1294]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1295]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1296]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1297]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1298] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [1299]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1300] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide, [1301]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1302] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide, [1303]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro -ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1304] 4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide, [1305]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1306]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1307]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1308]
4-Methyl-2-(4-methyl-thiazol-2-yl)-pyrimidine-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1309]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1310] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1311] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1312] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1313] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1314] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1315] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1316] 2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic
acid [3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1317] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1318]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(5-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1319]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1320]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1321]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1322] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [1323]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1324]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[3,2-c]pyridin-1-yl)-amide, [1325]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1326] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-2,2-diuoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide, [1327]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1328]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1329]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1330] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide, [1331]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1332]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
(3-difluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1333]
4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide,
[1334] 4-Methyl-[2,2']bipyrimidinyl-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[2,3-b]pyridin-1-yl]-amide, [1335]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-trifluoro methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1336]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(5-difluoromethyl -pyrrolo[3,2-b]pyridin-1-yl)-amide, [1337]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide, [1338]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[3,2-c]pyridin-1-yl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoro methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide, [1340]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide, [1341]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2-difluoro-ethyl)-pyrrolo[3,2-b]pyridin-1-yl]-amide, [1342]
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl) -pyrrolo[3,2-b]pyridin-1-yl]-amide,
[1343] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-amide,
[1344] 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid
[3-(2,2,2-trifluoro-ethyl)-pyrrolo[2,3-c]pyridin-1-yl]-amide,
[1345] 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, [1346]
2-(4-Chloro-thiazol-2-yl)-4-methyl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide, and [1347]
4-Methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid
(3-difluoromethyl-indol-1-yl)-amide.
In Vitro Assay Protocols to Identify Inhibitors of Hematopoietic
PGD2 Synthase
[1348] The compounds of the present invention can be tested for
enzymatic inhibiting activity against PGD2 Synthase according to
either one of the following assays.
Assay 1: Fluorescence Polarization Assay
[1349] As described in PCT publication WO 2004/016223, Example
II.
Assay 2: Enzyme Immunoassay (EIA) Method
I. Assay Solutions
[1350] a. Preparation of 0.1M K.sub.2HPO.sub.4/KH.sub.2PO.sub.4
buffer (pH 7.4) [1351] Prepare 0.1 M KH.sub.2PO.sub.4 from 1M
KH.sub.2PO.sub.4 (Sigma, Cat# P-8709) [1352] Prepare 0.1 M
K.sub.2HPO.sub.4 from powder of K.sub.2HPO.sub.4 (Fisher,
BP363-500) [1353] Mix 0.1 M K.sub.2HPO.sub.4 with 0.1 M
KH.sub.2PO.sub.4 to adjust pH to 7.4. [1354] b. Preparation of 0.5%
.gamma.-globulin [1355] Add 0.1 g of .gamma.-globulin (Sigma, Cat#
G-5009) to 20 mL 0.1 M K.sub.2HPO.sub.4/KH.sub.2PO.sub.4 buffer (pH
7.4) and make 1-mL/vial aliquots and store in -80.degree. C. [1356]
c. Preparation of 100 mM GSH [1357] Add 307 mg of GSH (Sigma, Cat#
G-6529) to 10 mL 0.1 M K.sub.2HPO.sub.4/KH.sub.2PO.sub.4 buffer (pH
7.4) and store at -80.degree. C. [1358] d. Preparation of Reaction
buffer: [1359] 198 mL of 0.1M K.sub.2HPO.sub.4/KH.sub.2PO.sub.4
buffer (pH 7.4) [1360] 2 mM GSH--Prepared from 100 mM GSH [1361]
0.4 g Glycerol [1362] 2 mL of 0.5% .gamma.-globulin [1363] Add 0.4
g of glycerol and 2 mL of 0.5% .gamma.-globulin to 198 mL of 0.1 M
K.sub.2HPO.sub.4/KH.sub.2PO.sub.4 [1364] buffer (pH7.4). [1365] Add
0.4 mL of 100 mM GSH to 19.6 mL reaction buffer before the assay
(enough for two 96-well plates). [1366] e. Preparation of
FeCl.sub.2/citric acid stopping solution: (8 mg/mL FeCl.sub.2, 0.1
M citric acid) [1367] Add 40 mg fresh FeCl.sub.2 (IGN, Cat# 158046)
to 5 mL 0.1 M citric acid (Sigma, Cat# C0759). [1368] f.
Preparation of MOX reagent: [1369] 10% EtOH--Add 1 mL of EtOH to 9
mL of ultra pure H.sub.2O [1370] Dissolve 0.1 g of methoxyl amine
(Cayman, Cat# 400036/) in 10% EtOH (10 mL). [1371] Add 0.82 g of
sodium acetate (Cayman, Cat#400037) to MOX solution and
dissolve.
II. Materials and Method
[1371] [1372] Dimethylsulfoxide (DMSO; Sigma; Cat# D2650) [1373]
Prostaglandin D2-MOX express EIA kit (Caymen Chemical, Catalog No.
500151)
[1374] Before the assay, cool down 10 mL of acetone in
polypropylene tubes and empty 96 well plates in ice. All the
procedures except compound dilution are performed on ice.
III. Compound Dilution
[1375] 1. Dilute compound in DMSO
TABLE-US-00001 [1375] Vol of DMSO stock Compound concentration
solution (.mu.L) DMSO (.mu.L) (mM) 4 .mu.L of 10 mM 6 .mu.L 4 3
.mu.L of 4 mM 6 .mu.L 1.3333 3 .mu.L of 1.33 mM 6 .mu.L 0.4444 3
.mu.L of 0.44 mM 6 .mu.L 0.1481 3 .mu.L of 0.148 mM 6 .mu.L 0.0494
3 .mu.L of 0.049 mM 6 .mu.L 0.0165 3 .mu.L of 0.016 mM 6 .mu.L
0.0055
[1376] 2. Dilute 2 .mu.L of each above concentration of compound to
38 .mu.L of reaction buffer in 96-well plates and mix.
IV. Enzyme and Substrate Solution Preparation
[1376] [1377] 1 Preparation of 0.39 ng/.mu.L enzyme solution (0.35
ng/.mu.L at final after compound addition). [1378] Mix 4 .mu.L of 4
mg/mL human h-PGDS with 396 .mu.L of reaction buffer (to give
enzyme concentration 40 .mu.g/mL). Add 46.8 .mu.L of 40 .mu.g/mL
h-PGDS to 4.753 mL of reaction buffer to give a total volume of 4.8
mL [1379] 2. Preparation of Substrate Solution (PGH2): Add 0.375 mL
of 0.1 mg/mL of PGH2 to 1.625 mL acetone.
V. Enzyme Reaction:
[1379] [1380] 1. Add 60 .mu.L of enzyme solution to compound well
and positive control (without compound) in U-bottom polypropylene
plate on ice. [1381] 2. Add 60 .mu.L of reaction buffer and 6.6
.mu.L of 5% DMSO in reaction buffer into negative control wells in
the plate. [1382] 3. Add 6.6 .mu.L of diluted compound in reaction
buffer to the compound wells and mix. [1383] 4. Add 6.6 .mu.L of 5%
DMSO in reaction buffer to the positive control well. [1384] 5.
Incubate the plate in ice for at least 30 min. [1385] 6. Add 20
.mu.L of substrate (PGH2) solution to compound, negative and
positive control wells in the U-bottom 96 well plate on ice. [1386]
7. Dry the plate in cold room for about 25-28 min. [1387] 8.
Pipette 45 .mu.L of enzyme solution (above) into 96-wells with
dried PGH2 and mix 3 times. Incubate on the ice for 1 min. [1388]
9. Add 45 .mu.L of FeCl.sub.2 solution into each wells and mix.
[1389] 10. Add 90 .mu.L of MOX solution and mix. [1390] 11.
Incubate for 30 min at 60.degree. C. [1391] 12. Dilute the samples
2500.times. with EIA buffer.
VI. EIA Assay
[1391] [1392] Perform the assay according to the procedure in EIA
kit provided by Cayman. Total PGD2 levels (pg/mL) were determined
in the samples by EIA kits (Caymen Chemical, Catalog No.
500151)
Calculate Amount of PGD2 as Below
[1392] [1393] Calculated % Positive control according to the
equation below;
[1393] % Positive control=(Compound value-Negative
control)/(Positive value-Negative control value).times.100.
% Positive control = ( Compound value - Negative control ) (
Positive value - Negative control value ) .times. 100 ##EQU00001##
[1394] Compound value=PGD2 levels (pg/mL) obtained from the
standard curve in EIA assay for the samples with compound [1395]
Negative control value=PGD2 levels (pg/mL) obtained from the
standard curve in EIA assay for the samples without enzyme [1396]
Positive control value=PGD2 levels (pg/mL) obtained from the
standard curve in EIA assay for the samples with enzyme but without
compound [1397] IC.sub.50s are determined by excel fit to get the x
value when y=1/2Ymax using 4 parameter logistic model for the
IC.sub.50 curves.
Results
[1398] Compounds within the scope of the invention produce 50%
inhibition in the Fluorescence Polarization Assay or the EIA assay
at concentrations within the range of about 1 nanomolar to about 30
micromolar, particularly about 1 nanomolar to about 1 micromolar,
and more particularly about 1 nanomolar to about 100 nanomolar.
IC.sub.50s obtained by EIA assay for some of the examples are shown
at the end of each of those examples.
[1399] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof.
* * * * *